Efficacy of GSK Biologicals' Candidate Tuberculosis (TB) Vaccine GSK 692342 Against TB Disease, in Adults Living in a TB Endemic Region
Phase: PHASE2
Conditions: Tuberculosis, Tuberculosis Vaccines
Sponsor: GlaxoSmithKline

CONFIDENTIAL
29-JAN-2014
1
Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut 89
1330 Rixensart, Belgium
Primary Study vaccine and 
number
GlaxoSmithKline (GSK) Biologicals’ candidate 
recombinant Mycobacterium tuberculosis vaccine, 
M72/AS01E (GSK 692342)
Other study vaccine/product
Placebo
eTrack study number and 
Abbreviated Titles
115616 (TUBERCULOSIS-018)
Date of protocol
Final: 29 May 2012
Date of protocol amendment 1
Amendment 1 Final: 20 July 2012
Date of protocol amendment 2
Amendment 2 Final: 10 September 2012
Date of protocol amendment 3
Amendment 3 Final: 11 December 2012
Date of protocol amendment 4
Amendment 4 Final: 26 March 2013
Date of protocol amendment 5
Amendment 5 Final: 29 January 2014
Title
(Amended: 29 January 2014)
Efficacy of GSK Biologicals’ candidate 
tuberculosis (TB) vaccine GSK 692342 against TB 
disease, in adults living in a TB endemic region
Detailed Title
(Amended: 29 January 2014)
A phase IIb, double-blind, randomised, placebo-
controlled study to evaluate the efficacy, safety and 
immunogenicity of GSK Biologicals’ candidate 
tuberculosis (TB) vaccine GSK 692342 against TB 
disease, in adults aged 18-50 years, living in a TB 
endemic region.
Co-ordinating author(s)
, Scientific Writer, XPE Pharma & 
Science for GSK Biologicals
Contributing authors GSK 
Biologicals
(Amended: 29 January 2014)
!
, Clinical Research and 
Development Lead
!
, Project Statistician
!
, Study Delivery Manager
!
, Project Delivery Lead
!
, Project Manager Clinical 
Readouts
!
, Safety Physician
!
, Study Data Manager
!
, Senior Manager Regulatory 
Affairs
!
, Global Regulatory Lead
Contributing Authors Aeras
(Amended: 29 January 2014)
!
, President & Chief Executive
Officer
!
, Director Clinical Development
GlaxoSmithKline Biologicals will act as the regulatory sponsor for this trial.
GSK Biologicals’ Protocol DS v 14.0
Copyright 2012 - 2014 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
1
29-JAN-2014
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
2
Protocol Amendment 5 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
115616 (TUBERCULOSIS-018)
Date of protocol amendment
Amendment 5 Final: 29 January 2014
Detailed Title 
(Amended: 29 January 2014)
A phase IIb, double-blind, randomised, placebo-
controlled study to evaluate the efficacy, safety and 
immunogenicity of GSK Biologicals’ candidate 
tuberculosis (TB) vaccine GSK 692342 against TB 
disease, in adults aged 18-50 years, living in a TB 
endemic region.
Sponsor signatory
Didier Lapierre, Vice President Global Vaccine 
Development - Malaria, Tuberculosis and Adjuvants 
Signature
Date
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
2
29-JAN-2014
- ----------------Checksum----------------!Ver.!Created On -   -
680e97c95ac54ffa4525253412affca36f653fc3 2.0 2/7/2014 1:02:18 PM -   -
---------------------------------------------------------------------------- -
For internal use only

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
3
Protocol Amendment 5 Rationale
Amendment number:
Amendment 5
Rationale/background for changes:
Optimized study design and sample size by increasing event rate by focussing on 
IGRA positive subjects. Baseline screening for pulmonary TB as precautionary 
safety measures. Separate protocol for biobanking of blood samples for future 
research on biological correlates for TB disease.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
3
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
4
Protocol Amendment 5 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccine(s)/product(s) and other study-related 
duties and functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative. 

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s). 

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine(s)/product(s), and more generally about 
his/her financial ties with the sponsor. GSK Biologicals will use and disclose the 
information solely for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
4
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
5
eTrack study number and 
Abbreviated Title
115616 (TUBERCULOSIS-018)
Date of protocol amendment
Amendment 5 Final: 29 January 2014
Detailed Title
A phase IIb, double-blind, randomised, placebo-
controlled study to evaluate the efficacy, safety and 
immunogenicity of GSK Biologicals’ candidate 
tuberculosis (TB) vaccine GSK 692342 against TB 
disease, in adults aged 18-50 years, living in a TB 
endemic region.
Investigator name
Signature
Date
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
5
29-JAN-2014
- ----------------Checksum----------------!Ver.!Created On -   -
680e97c95ac54ffa4525253412affca36f653fc3 2.0 2/7/2014 1:02:18 PM -   -
---------------------------------------------------------------------------- -
For internal use only

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
6
Sponsor Information
1.
Sponsor
GlaxoSmithKline Biologicals
Rue de l’Institut 89
1330 Rixensart, Belgium
2.
Sponsor Medical Expert for the Study
Refer to the local study contact information document.
3.
Sponsor Study Monitor
Refer to the local study contact information document.
4.
Sponsor Study Contact for Reporting of a Serious Adverse Event
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to Protocol 
Section 9.3.2.
5.
GSK Biologicals’ Central Safety Physician On-Call Contact information for 
Emergency Unblinding
GSK Biologicals Central Safety Physician and Back-up Phone contact: refer to 
Protocol Section 9.7.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
6
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
7
SYNOPSIS
Detailed Title
(Amended: 29 January 
2014)
A phase IIb, double-blind, randomised, placebo-
controlled study to evaluate the efficacy, safety and 
immunogenicity of GSK Biologicals’ candidate 
tuberculosis (TB) vaccine GSK 692342 against TB 
disease, in adults aged 18-50 years, living in a TB 
endemic region.
Indication
(Amended: 29 January 
2014)
Vaccination against tuberculosis (TB) disease in adults 
aged 18 to 50 years, living in a TB endemic region.
Rationale for the study 
and study design

Rationale for the study
The burden of Mycobacterium tuberculosis (Mtb) disease, 
particularly when compounded by Human 
Immunodeficiency virus (HIV)-infection and the 
emergence of multi-drug resistant (MDR) and 
extensively-drug resistant strains (XDR), is significant in 
TB endemic countries/regions. In 2010, approximately 
40% of TB cases were reported in India and China, of 
which up to 80% were pulmonary in nature [WHO, 
2011]. Africa accounted for a further 24% of cases (of 
which 25% were in South Africa), with most cases in 
young adults. 
Prevention of TB disease is not only preferable to 
treatment of the disease for public health reasons, but an 
effective prophylactic TB vaccine would also lead to a 
considerable return in health benefits. In TB endemic 
settings the incidence of pulmonary TB disease is higher
in people who have been infected with Mtb as evidenced 
by a positive Interferon gamma release assay (IGRA). 
For the present first phase II proof-of-concept trial 
focussing on this IGRA+ adult population maximizes 
the trial efficiency by increasing the event rate in the 
control group.
(Amended: 29 January 2014)
This Phase IIb study aims at collecting initial efficacy 
data and gathering further safety and immunogenicity 
data on the M72/AS01E vaccine candidate in adults living 
in a TB endemic region. (Amended: 29 January 2014)

Rationale for the study design
This Phase IIb study is designed to evaluate the protective 
efficacy of the M72/AS01E candidate TB vaccine against 
definite pulmonary TB disease not associated with HIV-
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
7
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
8
infection, versus placebo, following 2 injections given 
one month apart. The protective efficacy will be 
evaluated in baseline IGRA positive adults living in a TB 
endemic region aged 18-50 years, i.e. in an age range 
where the incidence of TB is high. (Amended: 29 
January 2014)
This study is an international, multicentre, phase IIb, 
double-blind, randomized, controlled trial. There will be 
follow-up for efficacy for up to 3 years after vaccination 
via regular visits or contacts to screen for possible TB. 
Subjects will also be asked to recognise signs and 
symptoms compatible with TB disease and to self-report
for clinical evaluation. Subjects with clinical suspicion of 
pulmonary TB will be assessed with confirmatory 
diagnostic testing using a Nucleic Acid Amplification 
Test (Xpert MTB/RIF assay, Cepheid) and 
microbiological culture. Subjects diagnosed with TB will 
be referred for TB treatment according to local clinical 
practice. (Amended: 29 January 2014)
The primary objective of this study is to evaluate the 
protective efficacy of two doses of the M72/AS01E
candidate vaccine against Definite pulmonary TB disease 
not associated with HIV-infection, as compared to 
placebo. To minimize the potential confounding effect of 
HIV infection in the study population, HIV testing will 
be performed at screening and only HIV negative 
subjects will be enrolled. Additionally, when a subject is 
diagnosed with TB, an HIV test (and pre-test counselling)
will be performed to rule out HIV co-infection. When a 
subject is diagnosed with HIV at the time of TB 
diagnosis, additional tests will be performed to measure 
CD4 cell counts to assess the severity of the infection and 
decide on the appropriate treatment regimen. HIV-
positive subjects will be referred for HIV treatment 
according to local clinical practice. (Amended: 29 
January 2014)
Participating sites will use standardised case definitions 
for efficacy endpoints and a structured approach to case-
assessment as outlined in this study protocol will be used.
An Independent Data Monitoring Committee (IDMC) has 
been constituted for this study to perform periodic safety 
reviews of the safety data. (Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
8
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
9
A sub-cohort of subjects will be selected for specific 
follow-up for safety (solicited adverse events [AE] and 
selected Biochemistry and Complete Blood Count 
[CBC]) and immunogenicity. Unsolicited AEs, serious 
adverse events (SAEs), potential immune-mediated 
diseases (pIMDs), AEs leading to withdrawal and 
pregnancies will be recorded for all subjects.(Amended:
29 January 2014)

Rationale for the use of placebo
There is currently no established TB vaccine with 
recognised efficacy in the age range considered for this 
study. The use of a control group is mandatory for 
meeting the primary objective.
The use of an active vaccine as control has been 
evaluated but introduces significant unblinding risks as 
the presentation, schedule or indications are different 
from the M72/AS01E vaccine.
Objectives
(Amended:29 January 
2014)
Primary

To evaluate the protective efficacy of two doses of 
the M72/AS01E candidate vaccine against Definite 
pulmonary TB disease not associated with HIV-
infection, meeting the first case definition, as 
compared to placebo.
Success criterion:
The lower limit of the 90% two-sided confidence interval 
(CI) for the VE (using a Cox regression model) against 
first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the first case 
definition, is above 0%. (Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
9
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
10
Secondary
Efficacy:

To evaluate the protective efficacy of two doses of 
the M72/AS01E candidate vaccine against Definite 
Xpert MTB/Rif positive pulmonary TB disease not 
associated with HIV-infection, meeting the second 
case definition, as compared to placebo.
If the primary objective is met, this secondary objective 
will be analysed with the following success criterion:
The lower limit of the 90% two-sided CI for the VE (using 
a Cox regression model) against first occurrence of 
Definite pulmonary TB disease not associated with HIV-
infection, meeting the second case definition, is above 
0%. (Amended: 29 January 2014)

To evaluate the protective efficacy of two doses of 
the M72/AS01E candidate vaccine against Definite 
pulmonary TB disease not associated with HIV-
infection, meeting the third case definition, as 
compared to placebo.

To evaluate the protective efficacy of two doses of 
the M72/AS01E candidate vaccine against 
Microbiological pulmonary TB disease meeting the 
fourth case definition, as compared to placebo.

To evaluate the protective efficacy of two doses of 
the M72/AS01E candidate vaccine against Clinical 
TB disease meeting the fifth case definition, as 
compared to placebo.
Safety:

To assess the safety and reactogenicity of two doses 
of the M72/AS01E candidate vaccine.
Immunogenicity:

To assess the immunogenicity of two doses of the 
M72/AS01E candidate vaccine.
Study design

Phase IIB, randomised, double-blind, controlled, 
multi-centric, efficacy study with two parallel 
groups.

Duration of the study: the duration of the study will 
be approximately 37 months for each subject from 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
10
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
11
screening to end of efficacy follow-up.

Epoch 001: Primary starting at Visit 1 (screening 
visit) and ending at Visit 10 (Month 36).

Study groups: study groups and treatments foreseen
in this study are presented in Synopsis Table 1 and 
Synopsis Table 2.
Synopsis Table 1
Study groups and epochs foreseen in the study (Amended: 29 
January 2014)
Study groups
Number of subjects
Age (Min/Max)
Epoch 001
M72AS01
1753
18 years - 50 years
x
Control
1753
18 years - 50 years
x
Synopsis Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine/Product name
Study Groups
M72AS01
Control
M72/AS01E
M72
X
AS01E
X
Placebo
Placebo pellet
X
Placebo adjuvant
X

Blinding: double-blind (Synopsis Table 3).
Synopsis Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
double-blind

Vaccination schedule: Subjects will receive 2 doses 
of M72/AS01E or placebo, according to their random 
assignment, one month apart (Day 0 and Day 30) by 
intramuscular injection in the deltoid region of the 
arm.

Treatment allocation: Randomised 1:1. 
Randomisation will occur at the day of first 
vaccination (Day 0).

Control: placebo control.

Sampling schedule (Amended: 29 January 2014):

Blood samples will be collected in the safety and 
immune sub-cohort for evaluation of 
biochemistry/haematology parameters (Days 0, 7, 
30 and 37), CMI responses (Days 0, 60 and Years 
1, 2 and 3) and humoral immune responses (Days 
0, 60 and Years 1, 2 and 3). Vitamin D levels will 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
11
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
12
be measured at Day 0.

Blood samples will be collected for QFTG testing 
at screening for all subjects.

A respiratory sputum sample will be collected 
prior to vaccination in all subjects for nucleic 
acid amplification test to rule out pulmonary 
TB.

Blood samples will be collected for initial HIV 
testing at screening for all subjects. Repeat HIV 
testing will be performed at the last study visit 
V9, unless the subject has been confirmed HIV 
positive before V9.

Whenever a subject is diagnosed with TB 
disease, blood samples will be collected for HIV 
testing and HbA1c measurement. In addition, if 
a subject is HIV-positive, blood samples will be 
collected to determine CD4 cell counts.

Type of study: self-contained.

Data collection: Electronic Case Report Form 
(eCRF). - Inform™ (Amended: 29 January 2014)

Safety monitoring: an Independent Data Monitoring 
Committee (IDMC), operating under a charter, has 
been constituted for this study to oversee the study. 
They will perform safety reviews twice a year, or 
more frequently if deemed necessary on an ongoing 
basis for the duration of the study. (Amended: 29 
January 2014)
Case Definitions
First case definition – Definite pulmonary TB, not 
associated with HIV-infection

A subject with clinical suspicion* of pulmonary TB 
disease, with Mtb complex identified from a sputum 
specimen, taken before initiation of TB treatment, by 
Xpert MTB/RIF and/or microbiological culture and 
confirmed HIV-negative at the time of TB diagnosis.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
12
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
13
Second case definition –Definite Xpert MTB/Rif 
positive pulmonary TB, not associated with HIV-
infection

A subject with clinical suspicion* of pulmonary TB 
disease, with Mtb complex identified from a sputum 
specimen, taken before initiation of TB treatment, by 
Xpert MTB/RIF and confirmed HIV-negative at the 
time of TB diagnosis.
Third case definition – Definite pulmonary TB, not 
associated with HIV-infection

A subject with clinical suspicion* of pulmonary TB 
disease, with Mtb complex identified from a sputum 
specimen, taken up to four weeks after initiation of 
TB treatment, by Xpert MTB/RIF and/or 
microbiological culture and confirmed HIV-negative 
at the time of TB diagnosis.
Fourth case definition –Microbiological pulmonary TB
(Amended: 29 January 2014)

A subject with clinical suspicion* of pulmonary TB 
disease, with Mtb complex identified from a sputum 
specimen, taken up to four weeks after initiation of 
TB treatment, by Xpert MTB/RIF and/or 
microbiological culture.
*Clinical suspicion of pulmonary TB is defined as a 
subject presenting with one or more of the following 
symptoms: unexplained cough > 2 weeks, unexplained 
fever > 1 week, night sweats, unintentional weight loss, 
pleuritic chest pains, haemoptysis, fatigue or shortness of 
breath on exertion.
Fifth case definition – Clinical TB
A subject for whom a clinician has diagnosed TB disease 
and has decided to treat the patient with TB treatment.
Number of subjects
Approximately 3506. (Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
13
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
14
Endpoints
Primary

Incident cases of Definite Pulmonary TB disease 
not associated with HIV-infection, meeting the first 
case definition.
Over a period starting 1 month post-dose 2 and 
lasting up to 35 months post last vaccination.
Secondary
Efficacy

Incident cases of Definite Xpert MTB/Rif positive
Pulmonary TB disease not associated with HIV-
infection, meeting the second case definition.
Over a period starting 1 month post-dose 2 and 
lasting up to 35 months post last vaccination.

Incident cases of Definite Pulmonary TB disease
meeting the third case definition.
Over a period starting 1 month post-dose 2 and 
lasting up to 35 months post last vaccination.

Incident cases of Microbiological Pulmonary TB 
disease meeting the fourth case definition.
Over a period starting 1 month post-dose 2 and 
lasting up to 35 months post last vaccination

Incident cases of Clinical TB disease meeting the 
fifth case definition.
Over a period starting 1 month post-dose 2 and 
lasting up to 35 months post last vaccination
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
14
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
15
Safety

Occurrence of SAEs.
During the entire study period

Occurrence of unsolicited AEs.
During the 30 day follow-up period following 
vaccination (day of vaccination and 29 subsequent 
days after each vaccine dose)

Occurrence of solicited local and general AEs in the 
safety and immune sub-cohort.
During the 7 day follow-up period following 
vaccination (day of vaccination and 6 subsequent 
days after each vaccine dose).

Occurrence of all pIMDs.
Over a period starting at Day 0 until 6 months post-
dose 2.

Occurrence of grade 2 haematological and 
biochemical, in the safety and immune sub-cohort,
levels at:
Days 0, 7, 30 and 37
(Amended: 29 January 2014)
Immunogenicity

Evaluation of CMI responses with respect to 
components of the study vaccine, in the safety and 
immune sub-cohort:

Determined by the frequency of M72-specific 
CD4+/CD8+ T-cells per million cells identified 
after in vitro stimulation, as expressing any 
combination of immune markers among 
CD40L, IL-2, IFN-and TNF-.. (Amended: 29 
January 2014)
Timepoints: prior to dose 1 (Day 0) and post-dose 2 (Day 
60, Years 1, 2 and 3)

Evaluation of humoral immune responses with 
respect to components of the study vaccine, in the 
safety and immune sub-cohort:

Determined by M72-specific antibody titres as 
measured by ELISA.

Determined by seropositivity rates as measured 
by ELISA.
Timepoints: prior to dose 1 (Day 0) and post-dose 2 (Day 
60, Years 1, 2 and 3).
(Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
15
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
16
TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................6
SYNOPSIS......................................................................................................................7
LIST OF ABBREVIATIONS...........................................................................................25
GLOSSARY OF TERMS ...............................................................................................29
TRADEMARKS .............................................................................................................33
1.
INTRODUCTION....................................................................................................34
1.1.
Background ................................................................................................34
1.2.
Collaboration between GSK Biologicals and Aeras.....................................35
1.3.
Rationale for the study and study design ....................................................35
1.3.1.
Rationale for the study.................................................................35
1.3.2.
Rationale for the study design......................................................36
1.3.3.
Rationale for the use of placebo ..................................................37
2.
OBJECTIVES.........................................................................................................38
2.1.
Primary objective ........................................................................................38
2.2.
Secondary objectives..................................................................................38
3.
STUDY DESIGN OVERVIEW ................................................................................40
4.
CASE DEFINITIONS..............................................................................................43
5.
STUDY COHORT...................................................................................................44
5.1.
Number of subjects/centres ........................................................................44
5.2.
Inclusion criteria for enrolment....................................................................45
5.3.
Exclusion criteria for enrolment...................................................................46
6.
CONDUCT OF THE STUDY ..................................................................................47
6.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................47
6.2.
Subject identification and randomisation of treatment .................................48
6.2.1.
Subject identification....................................................................48
6.2.2.
Randomisation of treatment.........................................................48
6.2.2.1.
Randomisation of supplies..........................................48
6.2.2.2.
Treatment allocation to the subject.............................48
6.2.2.2.1.
Study group and treatment 
number allocation ...................................48
6.2.2.2.2.
Treatment number allocation for 
subsequent doses ..................................49
6.2.3.
Allocation of subjects to assay subsets........................................49
6.3.
Method of blinding ......................................................................................49
6.4.
General study aspects ................................................................................49
6.4.1.
Surveillance for safety and efficacy..............................................49
6.4.1.1.
Active follow-up for safety and efficacy.......................49
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
16
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
17
6.4.1.2.
Passive follow-up for efficacy .....................................50
6.4.2.
Diagnostic procedures for the detection of suspected 
pulmonary TB ..............................................................................50
6.4.3.
Diagnostic procedures for suspected extra-pulmonary TB...........51
6.4.4.
Procedures for fatalities ...............................................................51
6.4.5.
Safety Monitoring Plan.................................................................52
6.4.5.1.
Safety Review Team ..................................................52
6.4.5.2.
Independent Data Monitoring Committee ...................52
6.4.5.3.
Planned safety review (Amended: 29 January 
2014)..........................................................................52
6.4.5.4.
Rules for vaccination (Amended: 29 January 
2014)..........................................................................53
6.5.
Outline of study procedures ........................................................................55
6.6.
Detailed description of study procedures ....................................................58
6.6.1.
Informed consent.........................................................................58
6.6.2.
Check inclusion and exclusion criteria .........................................58
6.6.3.
Collect demographic data ............................................................58
6.6.4.
Collect history of TB household contacts .....................................58
6.6.5.
Medical history.............................................................................59
6.6.6.
Physical examination ...................................................................59
6.6.7.
History directed physical examination..........................................59
6.6.8.
Urine pregnancy test....................................................................59
6.6.9.
Check contraindications to vaccination ........................................59
6.6.10.
Assess pre-vaccination body temperature ...................................60
6.6.11.
Study group and treatment number allocation..............................60
6.6.12.
Sampling......................................................................................60
6.6.12.1.
Blood sampling for safety and immune 
response assessments (Amended: 29 January 
2014)..........................................................................60
6.6.12.2.
Sputum sample collection for TB screening 
(Amended: 29 January 2014) .....................................61
6.6.12.3.
Sputum sample collection for TB diagnosis ................61
6.6.13.
TB disease capture......................................................................61
6.6.14.
Study Vaccine administration.......................................................62
6.6.15.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................62
6.6.16.
Study conclusion..........................................................................63
6.7.
Biological sample handling and analysis.....................................................63
6.7.1.
Use of specified study materials ..................................................64
6.7.2.
Biological samples.......................................................................64
6.7.2.1.
Protocol mandated testing and enpoints 
(Amended: 29 January 2014) .....................................64
6.7.3.
Laboratory assays .......................................................................65
6.7.4.
Biological samples evaluation per protocol (Amended: 29 
January 2014)..............................................................................66
6.7.4.1.
Diagnostic assays ......................................................66
6.7.4.2.
Immunological read-outs ............................................67
6.7.4.3.
Haematology/Biochemistry.........................................67
6.7.5.
Immunological correlates of protection.........................................68
7.
STUDY VACCINES AND ADMINISTRATION ........................................................69
7.1.
Description of study vaccines......................................................................69
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
17
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
18
7.2.
Storage and handling of study vaccines......................................................69
7.3.
Dosage and administration of study vaccines .............................................70
7.4.
Replacement of unusable vaccine doses....................................................70
7.5.
Contraindications to subsequent vaccination ..............................................71
7.6.
Concomitant medication/product and concomitant vaccination ...................71
7.6.1.
Recording of concomitant medications/products and 
concomitant vaccination...............................................................71
7.6.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from ATP analyses........................72
7.7.
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses .........................................................................72
8.
HEALTH ECONOMICS ..........................................................................................73
9.
SAFETY.................................................................................................................73
9.1.
Safety definitions ........................................................................................73
9.1.1.
Definition of an adverse event......................................................73
9.1.2.
Definition of a serious adverse event ...........................................74
9.1.3.
Solicited adverse events..............................................................75
9.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................76
9.1.5.
Adverse events of specific interest...............................................78
9.1.5.1.
Potential immune-mediated diseases .........................78
9.1.6.
Pregnancy ...................................................................................80
9.2.
Detecting and recording adverse events, serious adverse events 
and pregnancies .........................................................................................81
9.2.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies.....................................81
9.2.2.
Post-Study adverse events and serious adverse events..............83
9.2.3.
Evaluation of adverse events and serious adverse events...........83
9.2.3.1.
Active questioning to detect adverse events 
and serious adverse events........................................83
9.2.3.2.
Assessment of adverse events...................................84
9.2.3.2.1.
Assessment of intensity..........................84
9.2.3.2.2.
Assessment of causality .........................85
9.2.3.3.
Assessment of outcomes............................................86
9.2.3.4.
Medically attended visits.............................................86
9.3.
Reporting of serious adverse events, pregnancies, and other events .........86
9.3.1.
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals............................................86
9.3.2.
Contact information for reporting serious adverse events 
and other events to GSK Biologicals............................................87
9.3.3.
Completion and transmission of SAE reports to GSK 
Biologicals ...................................................................................87
9.3.3.1.
Back-up system in case the electronic SAE 
reporting system does not work..................................87
9.3.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals ...................................................................................88
9.3.5.
Reporting of pIMDs to GSK Biologicals........................................88
9.3.6.
Updating of SAE, pregnancy, and pIMD information after 
freezing of the subject’s eCRF.....................................................88
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
18
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
19
9.3.7.
Regulatory reporting requirements for serious adverse 
events..........................................................................................88
9.4.
Follow-up of adverse events, serious adverse events, and 
pregnancies................................................................................................89
9.4.1.
Follow-up of adverse events and serious adverse events............89
9.4.1.1.
Follow-up during the study..........................................89
9.4.1.2.
Follow-up after the subject is discharged from 
the study.....................................................................89
9.4.2.
Follow-up of pregnancies.............................................................90
9.5.
Treatment of adverse events ......................................................................90
9.6.
Unblinding...................................................................................................90
9.7.
Emergency unblinding ................................................................................90
9.8.
Subject card................................................................................................91
10. SUBJECT COMPLETION AND WITHDRAWAL.....................................................92
10.1.
Subject completion .....................................................................................92
10.2.
Subject withdrawal......................................................................................92
10.2.1.
Subject withdrawal from the study ...............................................92
10.2.2.
Subject withdrawal from investigational vaccine...........................93
10.3.
Extension study ..........................................................................................93
10.4.
Screen and baseline failures.......................................................................93
11. STATISTICAL METHODS......................................................................................94
11.1.
Primary endpoint.........................................................................................94
11.2.
Secondary endpoints ..................................................................................94
11.3.
Determination of sample size......................................................................95
11.4.
Study cohorts/data sets to be analysed ......................................................96
11.4.1.
Total vaccinated cohort................................................................96
11.4.2.
According-to-protocol cohort for analysis of safety.......................96
11.4.3.
According-to-protocol cohort for analysis of 
immunogenicity............................................................................96
11.4.4.
According-to-protocol cohort for analysis of efficacy ....................97
11.5.
Derived and transformed data.....................................................................97
11.6.
Analysis of demographics...........................................................................98
11.7.
Analysis of efficacy .....................................................................................98
11.8.
Analysis of immunogenicity.........................................................................99
11.8.1.
CMI and humoral immune responses ..........................................99
11.8.1.1.
Within groups assessment..........................................99
11.9.
Analysis of safety........................................................................................99
11.10. Interpretation of analyses..........................................................................100
11.11. Conduct of analyses .................................................................................101
11.11.1. Sequence of analyses................................................................101
12. ADMINISTRATIVE MATTERS .............................................................................102
12.1.
eCRF instructions (Amended: 29 January 2014).......................................102
12.2.
Study Monitoring by “The Collaboration”...................................................102
12.3.
Record retention .......................................................................................103
12.4.
Quality assurance.....................................................................................103
12.5.
Posting of information on publicly available clinical trial registers and 
publication policy ......................................................................................104
12.6.
Provision of study results to investigators .................................................104
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
19
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
20
13. COUNTRY SPECIFIC REQUIREMENTS.............................................................104
14. REFERENCES.....................................................................................................105
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
20
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
21
LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study (Amended: 29 
January 2014)........................................................................................41
Table 2
Study groups and treatment foreseen in the study .................................41
Table 3
Blinding of study epochs ........................................................................41
Table 4
Sub-cohorts............................................................................................44
Table 5
Distribution of subjects in the sub-cohort................................................49
Table 6
Safety holding rules for vaccination (Amended: 29 January 2014) .........54
Table 7
List of study procedures (Amended: 29 January 2014)...........................55
Table 8
Intervals between study visits for all subjects (Amended: 29 
January 2014)........................................................................................58
Table 9
Intervals between study visits specific for the safety and immune 
sub-cohort..............................................................................................58
Table 10
Biological samples (Amended: 29 January 2014)...................................64
Table 11
Humoral Immunity (Antibody determination)...........................................65
Table 12
Cell-Mediated Immunity (CMI) (Amended: 29 January 2014) .................65
Table 13
Diagnostic tests for pulmonary TB disease (Amended: 29 
January 2014)........................................................................................65
Table 14
Diagnostic tests for HIV (Amended: 29 January 2014) ...........................66
Table 15
Haematology, Serum Chemistry, Urine tests..........................................66
Table 16
Immunological read-outs (Amended: 29 January 2014) .........................67
Table 17
Biochemistry/haematology readouts.......................................................68
Table 18
Study vaccines.......................................................................................69
Table 19
Dosage and administration.....................................................................70
Table 20
Solicited adverse events (Amended: 29 January 2014)..........................75
Table 21
Toxicity grading table for laboratory abnormalities (Amended: 29 
January 2014)........................................................................................76
Table 22
List of potential immune-mediated diseases...........................................79
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
21
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
22
Table 23
Reporting periods for adverse events, serious adverse events 
and pregnancies.....................................................................................82
Table 24
Intensity scales for solicited symptoms in adults (Amended: 29 
January 2014)........................................................................................84
Table 25
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals .................................................87
Table 26
GSK Biologicals’ laboratories ...............................................................109
Table 27
Outsourced laboratories (Amended: 29 January 2014) ........................109
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
22
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
23
LIST OF FIGURES
PAGE
Figure 1
Age-related and sex-related incidence of tuberculosis ...........................36
Figure 2
Overview of the study design (Amended: 29 January 2014)...................40
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
23
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
24
LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS .....................................................................106
APPENDIX B CLINICAL LABORATORIES ................................................................109
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL.........................................................................................110
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
24
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
25
LIST OF ABBREVIATIONS
AB
Antibody
AE
Adverse Event
AIDS
Acquired Immune Deficiency Syndrome
ALT
Alanine aminotransferase
AP
Alkaline Phosphatase
AST
Aspartate aminotransferase
ATP
According-To-Protocol
-hCG
Beta-human chorionic gonadotropin
BCG
Bacille Calmette-Guérin
bkg
Background
CBC
Complete Blood Count
CD 4/8/40
Cluster of Differentiation 4/8/40
CD-40L
Cluster of Differentiation-40 Ligand
CFP-10
Culture Filtrate Protein-10
CI
Confidence Interval
CMI
Cell-Mediated Immune(ity)
DMSO
Dimethyl Sulfoxide
eCRF
electronic Case Report Form
EDD
Estimated Date of Delivery
EGA
Estimated Gestational Age
ELISA
Enzyme-Linked Immunosorbent Assay
EMA
European Medicine Agency
ESAT-6
Early Secretory Antigen Target-6
eTDF
electronic Temperature excursion Decision Form
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
25
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
26
EU/mL
ELISA units/millilitre
GCP
Good Clinical Practice
GMT
Geometric Mean Titre
GSK
GlaxoSmithKline
GVCL
Global Vaccines Clinical Laboratories
H0
Null Hypothesis
Ha
Alternative Hypothesis
Hb
Haemoglobin
HbA1c
Glycated haemoglobin
HIV
Human Immunodeficiency Virus
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
Intracellular Cytokine Staining
IEC
Independent Ethics Committee
IFN-
Interferon-gamma
IGRA
Interferon-Gamma Release Assay
IM
Intramuscularly
IMP(s)
Investigational Medicinal Product(s)
IDMC
Independent Data Monitoring Committee
IL-2
Interleukin-2
IL-13
Interleukin-13
IL-17
Interleukin-17
IPT
Izoniazid Preventive Therapy (Amended: 29 January 
2014)
IRB
Institutional Review Board
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
26
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
27
LMP
Last Menstrual Period
M72/AS01E
Mycobacterium tuberculosis fusion protein M72 with 
GSK’s proprietary adjuvant system containing MPL, 
QS21 with liposomes
MACDP
Metropolitan Atlanta Congenital Defects Program
MDR
Multi-drug resistant
MedDRA
Medical Dictionary for Regulatory Activities
MPL
3-O-desacyl-4’-MonophosPhoryl Lipid A
Mtb
Mycobacterium tuberculosis
PBMC
Peripheral Blood Mononuclear Cell
PI
Product Information
pIMD(s)
potential Immune-Mediated Disease(s)
PLT
Platelets
PPD
Purified Protein Derivative
PRE
Population Related Event
QFTG
QuantiFERON® TB Gold
QS21
A triterpene glycoside purified from the bark of the 
Quillaja saponaria tree
RR
Poisson Rate Ration
SAE
Serious Adverse Event
SAS
Statistical Analysis System
SBIR
Randomisation System on Internet
SDV
Source Document Verification
SMS
Short Message Service
SOC
System Organ Class
SPC
Summary of Product Characteristics
SPM
Study Procedures Manual
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
27
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
28
SRT
Safety Review Team
TB
Tuberculosis
TNF-
Tumour Necrosis Factor-alpha
TVC
Total Vaccinated Cohort
VA
Verbal Autopsy
VE
Vaccine Efficacy
WBC
White Blood Cells
WHO
World Health Organisation
XDR
Extensively drug-resistant
(Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
28
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
29
GLOSSARY OF TERMS
Adequate 
contraception:
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example:

abstinence from penile-vaginal intercourse, when this 
is their preferred and usual lifestyle,

oral contraceptives, either combined or progestogen 
alone,

injectable progestogen,

implants of etenogestrel or levonorgestrel,

estrogenic vaginal ring,

percutaneous contraceptive patches,

intrauterine device or intrauterine system,

male partner sterilisation prior to the female subject’s 
entry into the study, and this male is the sole partner 
for that subject,
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her medical 
history.

male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository),

male condom combined with a female diaphragm, 
either with or without a vaginal spermicide (foam, gel, 
film, cream, or suppository).
Adequate contraception does not apply to subjects of child 
bearing potential with same sex partners, when this is their 
preferred and usual lifestyle.
Adverse event:
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use of
a medicinal product, whether or not considered related to 
the medicinal product.
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes failure 
to produce expected benefits (i.e. lack of efficacy), abuse 
or misuse.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
29
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
30
Blinding:
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or when 
required in case of a serious adverse event. In a double 
blind study, the subject, the investigator and sponsor staff 
who are involved in the treatment or clinical evaluation of 
the subjects and the review or analysis of data are all 
unaware of the treatment assignment.
Clinical suspicion of 
pulmonary TB:
A subject has clinical suspicion of pulmonary TB when 
he/she presents with one or more of the following 
symptoms: unexplained cough > 2 weeks, unexplained 
fever > 1 week, night sweats, unintentional weight loss, 
pleuritic chest pains, haemoptysis, fatigue or shortness of 
breath on exertion.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
Epoch:
An epoch is a self-contained set of consecutive time points
or a single time point from a single protocol. Self-
contained means that data collected for all subjects at all 
time points within that epoch allows to draw a complete 
conclusion to define or precise the targeted label of the 
product. Typical examples of epochs are primary 
vaccinations, boosters, yearly immunogenicity follow-ups, 
and surveillance periods for efficacy or safety.
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, included 
in the according-to-protocol (ATP) analysis (see Sections 
7.6.2 and 11.4 for details on criteria for evaluability).
QFTG 
(Amended: 29 January 
2014)
The QFTG assay detects memory T-cell responses against 
Mtb as a surrogate for exposure to/infection with Mtb. The 
QFTG does not directly measure the presence of Mtb. The 
QFTG does not indicate whether the immune response of a 
subject was able to eliminate the bacteria or whether Mtb is
latently present
Immunological correlate 
of protection:
The defined humoral antibody response above which there 
is a high likelihood of protection in the absence of any host 
factors that might increase susceptibility to the infectious 
agent.
Investigational 
vaccine/product:
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
30
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
31
(Synonym of 
Investigational 
Medicinal Product)
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use.
Menarche:
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development and 
pubic hair growth. Menarche usually occurs within 1-2 
years of breast development, thelarche. However, a young 
female can become pregnant before her first menses. Thus, 
a conservative definition of non-childbearing potential in a 
pre-menarcheal female is a young female who has not yet 
entered puberty as evidenced by lack of breast 
development (palpable glandular breast tissue).
Menopause:
Menopause is the age associated with complete cessation 
of menstrual cycles, menses and implies the loss of 
reproductive potential by ovarian failure. A practical 
definition accepts menopause after 1 year without menses 
with an appropriate clinical profile at the appropriate age 
e.g. > 45 years.
Potential Immune-
Mediated Disease:
Potential immune-mediated diseases (pIMDs) are a subset 
of AEs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest which 
may or may not have an autoimmune aetiology.
Primary completion 
date:
The date that the final subject was examined or received an 
intervention for the purpose of final collection of data for 
the primary outcome, whether the clinical trial concluded 
according to the pre-specified protocol or was terminated.
Protocol amendment:
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description of 
a change(s) to or formal clarification of a protocol.’ GSK 
Biologicals further details this to include a change to an 
approved protocol that affects the safety of subjects, scope 
of the investigation, study design, or scientific integrity of 
the study.
Protocol administrative 
change:
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study.
Note: Any change that falls under the definition of a 
protocol amendment (e.g. a change that affects the safety 
of subjects, scope of the investigation, study design, or 
scientific integrity of the study) MUST be prepared as an 
amendment to the protocol.
Randomisation:
Process of random attribution of treatment to subjects in 
order to reduce bias of selection.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
31
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
32
Self-contained study:
Study with objectives not linked to the data of another 
study.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
Solicited adverse event:
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a specified 
post-vaccination follow-up period.
Sub-cohort:
A group of subjects for whom specific study procedures 
are planned as compared to other subjects.
Subject:
Term used throughout the protocol to denote an individual 
who has been contacted in order to participate or 
participates in the clinical study, either as a recipient of the 
vaccine(s)/product(s) or as a control.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
“The Collaboration”:
Refers to the joint collaboration between GSK Biologicals 
and Aeras. GSK will act as the sponsor of this study 
whereas Aeras will provide financial and operational 
support.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, identified 
by a unique number, according to the study randomisation 
or treatment allocation.
Treatment number:
A number identifying a treatment to a subject, according to 
the study randomisation or treatment allocation.
Unsolicited adverse 
event:
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited AE.
Xpert MTB/RIF:
The Xpert MTB/RIF is a Nucleic Acid Amplification Test 
to detect Mtb complex and resistance to rifampicin in 
sputum samples using the GeneXpert® technology from 
Cepheid.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
32
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
33
TRADEMARKS
The following trademarks are used in the present protocol.
Note: In the body of the protocol (including the synopsis), the names of the vaccines will 
be written without the superscript symbol ™ or ® and in italics.
Trademarks of the GlaxoSmithKline 
group of companies
Generic description
HavrixTM
Hepatitis A vaccine
BoostrixTM
Tetanus, Diphtheria, acellular Pertussis vaccine
Ditanrix™
Diphtheria and Tetanus vaccine
CervarixTM
Human Papillomavirus vaccine
TypherixTM
Typhoid vaccine
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
33
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
34
1.
INTRODUCTION
1.1.
Background
TB is the second leading cause of mortality worldwide, leading to about 1.3 million 
deaths a year [WHO, 2013]. It is estimated that a third of the world’s population is 
infected latently with the Mycobacterium tuberculosis (Mtb) bacilli. Although not more 
than 5-20% of infected individuals will become ill, the high number of infected people 
poses a great risk to individuals with reduced immunity who are at a higher risk for TB. 
The TB burden is compounded by the emergence of multi-drug resistant (MDR) and 
extensively-drug resistant (XDR) TB. Approximately 8.6 million incident cases of TB 
were reported in 2012 globally. Most TB cases were in Asia (mainly India and China)
and Africa (58% and 27% respectively). Asia refers to the WHO Regions of South-East 
Asia and the Western Pacific. Of these incident cases, an estimated 1.1 million (13%) 
were Human Immunodeficiency Virus (HIV) positive [WHO, 2013]. TB is the most 
common co-existing condition in people who die from Acquired Immune Deficiency 
Syndrome (AIDS). (Amended: 29 January 2014)
Prevention of TB disease is not only preferable to treatment of the disease for public 
health reasons, but an effective prophylactic TB vaccine would also lead to a 
considerable return in health benefits.
Bacille Calmette-Guerin (BCG), the only existing vaccine against TB, has been widely 
available for several decades. It is easy and cheap to produce, and when given to neonates 
or young children it is effective in preventing severe manifestations of disease such as 
meningeal TB and miliary TB. BCG appears to be less effective in preventing adult-onset 
TB. Since it became available, more than 3 billion people have received BCG. However,
studies have shown that protection against adult pulmonary TB in vaccinated individuals 
varies between 0 and 80% [Fine, 1995]. Indeed, protection against TB by BCG wanes 
over time and there is no evidence that it provides protection more than 10 years after 
vaccination [Sterne, 1998]. Also, BCG is contraindicated for individuals with impaired 
immunity including symptomatic HIV-infection, where the need to prevent TB is high 
[WHO, 2004].
Currently, TB is typically treated with a combination of antibiotics taken daily for a long 
period of time (6-12 months). Compliance is often incomplete, resulting in an increasing 
incidence of MDR- and XDR-TB. The ‘Directly Observed Treatment Strategy’ (DOTS) 
programme in TB endemic countries is currently providing treatment based on supervised 
therapy.
Drug resistant TB requires a multi-drug combination that is based on drug sensitivity 
testing results. Injectable drugs may be required and long durations of treatment may also 
be needed.
Taken together, the development of an efficacious prophylactic vaccine that prevents TB 
disease and development of active disease in individuals latently infected with Mtb may 
be the key element for successful control of TB in the long-term.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
34
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
35
GlaxoSmithKline (GSK) Biologicals is developing a vaccine to provide protective 
immunity against TB disease due to Mtb in children, adolescents and adults. The 
candidate vaccine selected for development is M72/AS01E. M72/AS01E is a recombinant 
fusion protein M72, derived from two immunogenic Mtb antigens, adjuvanted with 
GSK’s proprietary Adjuvant System AS01E.
To date, M72/AS01E has been evaluated in a series of Phase II studies in Purified Protein 
Derivative (PPD)-negative and -positive adults in South Africa, PPD-positive adults 
(BCG vaccinated) in The Philippines, healthy BCG vaccinated adolescents in South 
Africa and HIV-positive adults on Anti Retroviral Therapy (ART) in Switzerland. The 
vaccine was shown to have a clinically acceptable safety profile and was highly 
immunogenic producing antigen specific humoral and cellular immune responses in these 
populations. In subjects with concurrent Pulmonary TB disease receiving treatment the 
vaccination seemed to induced a higher incidence of grade 3 injection site reactions; 
this observation is under futher investigation. (Amended: 29 January 2014)
Please refer to the current Investigator Brochure for information regarding the pre-
clinical and clinical studies and the potential risks and benefits of M72/AS01E.
1.2.
Collaboration between GSK Biologicals and Aeras
This study is a joint collaboration between GSK Biologicals and Aeras, referred to as 
“The Collaboration” in the remainder of this document.
Established in 2003, Aeras is a non-profit biotechnology organization developing new 
generation tuberculosis vaccines and biologics with the aim of making products that are 
both efficacious and affordable in order to maximize public health impact. Aeras utilizes 
its broad capabilities and technologies in collaboration with a global consortium of 
partners, and has established expertise in vaccine development – from discovery and 
preclinical development through manufacturing, clinical testing and global regulatory 
affairs. Aeras’ highly skilled staff consists of nearly 150 in its headquarters in Rockville, 
Maryland and an additional 16 staff in its office in Cape Town, South Africa.
For this study, GSK Biologicals and Aeras are both providing financial support. GSK 
Biologicals will act as the regulatory sponsor while Aeras personnel are providing 
operational support for this study on behalf of the sponsor.
1.3.
Rationale for the study and study design
1.3.1.
Rationale for the study
The burden of Mtb disease, particularly when compounded by HIV-infection and the 
emergence of MDR and XDR strains, is significant in TB endemic countries/regions. In 
2010, approximately 40% of TB cases were reported in India and China, of which up to 
80% were pulmonary in nature [WHO, 2013]. Africa accounted for a further 24% of 
cases (of which 25% were in South Africa), with most cases in young adults.
Prevention of TB disease is not only preferable to treatment of the disease for public 
health reasons, but an effective prophylactic TB vaccine would also lead to a 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
35
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
36
considerable return in health benefits. In TB endemic settings the incidence of clinical 
TB disease is highest in people who have been infected with Mtb as evidenced by a 
positive Interferon gamma release assay (IGRA). For the present first phase II proof-
of-concept trial focussing on this IGRA+ adult population maximizes the trial 
efficiency by increasing the event rate in the control group. (Amended: 29 January 
2014)
This Phase IIb study aims at collecting initial efficacy data and gathering further safety 
and immunogenicity data on the M72/AS01E vaccine candidate in IGRA+ adults, healthy 
or with stable chonic medical condition(s), living in a TB endemic region. (Amended:
29 January 2014)
All study participants may be offered to consent to participate in a second and parallel 
study Sponsored by AERAS which aims to collect a supplemental set of pre- and post-
vaccination blood samples to constitute a Biobank. After completion of this study this 
Biobank will serve for investigations into biological correlates of risk for TB disease
and potentially correlates of protection. Please refer to this separate protocol for 
further information. (Amended:29 January 2014)
1.3.2.
Rationale for the study design
This study is designed to evaluate the protective efficacy of the M72/AS01E candidate TB
vaccine against definite pulmonary TB disease, versus placebo, following 2 injections 
given one month apart. The protective efficacy will be evaluated in IGRA+ adults living 
in a TB endemic region aged 18-50 years, i.e. in an age range where the incidence of TB
is high (Figure 1). (Amended: 29 January 2014)
Figure 1
Age-related and sex-related incidence of tuberculosis
Age- and gender- related incidence of TB in a hypothetical high tuberculosis incidence community with a large number 
of children and a low TB incidence community with a relatively small number of children [Donald, 2004].
This study is an international, multicentre, phase IIb, double-blind, randomized, 
controlled trial. There will be follow-up for efficacy for approximately 3 years after 
vaccination via regular visits or contacts to screen for possible TB. Subjects will also be 
asked to recognise signs and symptoms compatible with TB disease and to self-report for 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
36
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
37
clinical evaluation. Subjects with clinical suspicion of pulmonary TB will be assessed 
with confirmatory diagnostic testing using a Nucleic Acid Amplification Test (Xpert 
MTB/RIF assay, Cepheid) and microbiological culture. Subjects diagnosed with TB will 
be referred for TB treatment according to local clinical practice.
The primary objective of this study is to evaluate the protective efficacy of two doses of 
the M72/AS01E candidate vaccine against definite pulmonary TB disease not associated 
with HIV-infection, as compared to placebo. To avoid the potential confounding effect 
of HIV infection in the study population at baseline, HIV testing will be required to be 
negative at screening. Additionally, when a subject is diagnosed with TB, an HIV test 
(and pre-test counselling) will be performed to rule out HIV co-infection. When a subject 
is diagnosed with HIV at the time of TB diagnosis, additional tests will be performed to 
measure CD4 counts to assess the severity of the infection and decide on the appropriate 
treatment regimen. HIV-positive subjects will be referred for HIV treatment according to 
local clinical practice. (Amended: 29 January 2014)
Participating sites will use standardised case definitions for efficacy endpoints and a 
structured approach to case-assessment as outlined in this study protocol will be used.
An Independent Data Monitoring Committee (IDMC) has been constituted for this study 
to perform periodic safety reviews of the safety data. (Amended: 29 January 2014)
A sub-cohort of subjects will be selected for specific follow-up for safety (solicited 
adverse events (AE) and selected Biochemistry and Complete Blood Count [CBC]) and 
immunogenicity. Unsolicited AEs and large swelling reactions, serious adverse events 
(SAEs), potential immune-mediated diseases (pIMDs), AEs leading to withdrawal and 
pregnancies will be recorded for all subjects. (Amended: 29 January 2014)
1.3.3.
Rationale for the use of placebo
There is currently no established TB vaccine with recognised efficacy in the age range 
considered for this study. The use of a control group is mandatory for meeting the 
primary objective, i.e. evaluating the protective efficacy of the M72/AS01E vaccine 
candidate against definite pulmonary TB disease not associated with HIV-infection. 
The use of an active vaccine as control has been evaluated but it introduces significant 
unblinding risks as the presentation, schedule or indications are different for vaccines that 
could have been considered such as:

Havrix: 2 doses needed with a minimal 6 months interval, different appearance, and 
different volume per dose (1 mL)

Hepatitis B: 3-dose primary schedule needed, different appearance; 1-dose booster 
(not registered) required

Boostrix: 1-dose booster schedule, different appearance

Ditanrix: 3-dose primary schedule needed or 1-dose for booster, different appearance

Cervarix: only indicated in females, different appearance

Influenza: not recommended year round, 1-dose schedule, different appearance
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
37
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
38

Typherix: 1-dose schedule, different appearance
When using these vaccines as active control, an additional placebo (double-dummy 
placebo) would be required to match the dosing schedules of the investigational vaccine
and comparator vaccine, in order to maintain the blinding. Therefore, a placebo will be 
used as control.
Use of the placebo control and the double-blind, randomised study design, will allow to 
control for potential biases in the conduct of the study.
2.
OBJECTIVES
2.1.
Primary objective

To evaluate the protective efficacy of two doses of the M72/AS01E candidate 
vaccine against Definite pulmonary TB disease not associated with HIV-infection, 
meeting the first case definition, as compared to placebo.
Success criterion to be used for the primary objective:
The lower limit of the 90% two-sided confidence interval (CI) for the VE (using a 
Cox regression model) against first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the first case definition, is above 0%.
(Amended: 29 January 2014)
Refer to Section 4 for case definitions and Section 11.1 for the definition of the primary 
endpoint.
2.2.
Secondary objectives
Efficacy:

To evaluate the protective efficacy of two doses of the M72/AS01E candidate 
vaccine against Definite Xpert MTB/Rif positive pulmonary TB disease not 
associated with HIV-infection, meeting the second case definition, as compared to 
placebo.
If the primary objective is met, this secondary objective will be analysed using the 
following success criterion:
The lower limit of the 90% two-sided CI for the VE (using a Cox regression model) 
against first occurrence of Definite pulmonary TB disease not associated with HIV-
infection, meeting the second case definition, is above 0%. (Amended: 29 January 
2014)

To evaluate the protective efficacy of two doses of the M72/AS01E candidate 
vaccine against Definite pulmonary TB disease not associated with HIV-infection, 
meeting the third case definition, as compared to placebo.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
38
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
39

To evaluate the protective efficacy of two doses of the M72/AS01E candidate 
vaccine against Microbiological pulmonary TB disease meeting the fourth case 
definition, as compared to placebo.

To evaluate the protective efficacy of two doses of the M72/AS01E candidate 
vaccine against Clinical TB disease meeting the fifth case definition, as compared to 
placebo.
Safety:

To assess the safety and reactogenicity of two doses of the M72/AS01E candidate 
vaccine.
Immunogenicity:

To assess the immunogenicity of two doses of the M72/AS01E candidate vaccine.
Refer to Section 4 for case definitions and Section 11.2 for the definition of the secondary 
endpoints.
(Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
39
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
40
3.
STUDY DESIGN OVERVIEW
Figure 2
Overview of the study design (Amended: 29 January 2014)
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 6.5), are essential and required for 
study conduct.

Experimental design: Phase IIb, randomised, double-blind, controlled, multi-centre, 
efficacy study with two parallel groups.

Duration of the study: the duration of the study will be approximately 37 months
for each subject from screening up to end of efficacy follow-up.

Epoch 001: Primary starting visit 1 (screening visit) and ending visit 10 (Month 
36).

Study groups: Study groups and treatments foreseen in the study are presented in 
Table 1 and Table 2.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
40
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
41
Table 1
Study groups and epochs foreseen in the study (Amended: 29 January 
2014)
Study Groups
Number of subjects
Age (Min - Max) (age 
unit)
Epoch 001
M72AS01
1753
18 years - 50 years
x
Control
1753
18 years - 50 years
x
Table 2
Study groups and treatment foreseen in the study
Treatment name
Vaccine/Product name
Study Groups
M72AS01
Control
M72/AS01E
M72
X
AS01E
X
Placebo
Placebo pellet
X
Placebo adjuvant
X

Control: placebo control.

Vaccination schedule: Subjects will receive 2 doses of M72/AS01E or placebo, 
according to their random assignment, one month apart (Day 0 and Day 30) by 
intramuscular injection in the deltoid region of the arm.

Treatment allocation: Randomised 1:1. Randomisation will occur at the day of first 
vaccination (Day 0). Refer to Section 6.2 for a detailed description of the 
randomisation method.

Blinding: Double-blind (Table 3). Refer to Section 6.3 for method of blinding.
Table 3
Blinding of study epochs
Study Epochs
Blinding
Epoch 001
double-blind

Sampling schedule (Amended: 29 January 2014):

Blood samples will be collected in the safety and immune sub-cohort for 
evaluation of biochemistry/haematology parameters (Days 0, 7, 30 and 37), CMI 
responses (Days 0, 60 and Years 1, 2 and 3) and humoral immune responses
(Days 0, 60 and Years 1, 2 and 3). Vitamin D levels will be measured at Day 0.

Blood samples will be collected for QFTG testing at screening for all subjects.

A respiratory sputum sample will be collected prior to vaccination in all 
subjects for nucleic acid amplification test to rule out pulmonary TB.

Blood samples will be collected for initial HIV testing at screening for all 
subjects. Repeat HIV testing will be performed at the last study visit V9, unless 
the subject has been confirmed HIV positive before V9.

Whenever a subject is diagnosed with TB disease, blood samples will be 
collected for HIV testing and HbA1c measurement. In addition, if a subject is 
HIV-positive, blood samples will be collected to determine CD4 cell counts.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
41
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
42

Type of study: self-contained.

Data collection: electronic Case Report Form (eCRF – Inform™). (Amended: 29 
January 2014)

Safety monitoring: an IDMC, operating under a charter, has been constituted for 
this study to oversee the study. They will perform safety reviews twice a year, or 
more frequently if deemed necessary. (Amended: 29 January 2014)

Surveillance for efficacy: efficacy follow-up will be both active and passive (via 
self-reporting). Refer to Section 6.4.1 for a detailed description of the methods for 
surveillance for efficacy.

Diagnostic procedures for suspected Pulmonary TB: during the entire study (not 
for screening), when a subject presents with clinical suspicion of pulmonary TB, 
three respiratory sputum samples, preferably taken in the morning, within maximum 
a one week interval, must be collected for testing with Xpert MTB/RIF and 
microbiological culture. (Amended: 29 January 2014)
Refer to Section 6.4.2 for a detailed description of the diagnostic procedures for 
suspected pulmonary TB.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
42
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
43
4.
CASE DEFINITIONS
First case definition – Definite pulmonary TB, not associated with HIV-infection

A subject with clinical suspicion* of pulmonary TB disease, with Mtb complex 
identified from a sputum specimen, taken before initiation of TB treatment, by Xpert 
MTB/RIF and/or microbiological culture and confirmed HIV-negative at the time of 
TB diagnosis.
Second case definition –Definite Xpert MTB/Rif positive pulmonary TB, not 
associated with HIV-infection

A subject with clinical suspicion* of pulmonary TB disease, with Mtb complex 
identified from a sputum specimen, taken before initiation of TB treatment, by Xpert 
MTB/RIF and confirmed HIV-negative at the time of TB diagnosis.
Third case definition – Definite pulmonary TB, not associated with HIV-infection

A subject with clinical suspicion* of pulmonary TB disease, with Mtb complex 
identified from a sputum specimen, taken up to four weeks after initiation of TB 
treatment, by Xpert MTB/RIF and/or microbiological culture and confirmed HIV-
negative at the time of TB diagnosis.
Fourth case definition – Microbiological pulmonary TB

A subject with clinical suspicion* of pulmonary TB disease, with Mtb complex 
identified from a sputum specimen, taken up to four weeks after initiation of TB 
treatment, by Xpert MTB/RIF and/or microbiological culture.
*Refer to the GLOSSARY OF TERMS for a definition of clinical suspicion of 
pulmonary TB.
Fifth case definition – Clinical TB

A subject for whom a clinician has diagnosed TB disease and has decided to treat the 
patient with TB treatment.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
43
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
44
5.
STUDY COHORT
5.1.
Number of subjects/centres
Approximately 3506 men and women aged 18-50 years will be enrolled in the study. 
Enrolment will be terminated when target number of subjects is reached. (Amended: 29 
January 2014)
The study will be conducted in multiple TB endemic countries, in multiple enrolling 
centres. The study centres will be experienced in detecting TB and have access to TB 
treatment or have an established referral option for TB patients and HIV-infected 
individuals.
There will be one sub-cohort for safety/reactogenicity, and immunogenicity.
Approximately 450 eligible subjects from selected centres in multiple countries (2 or 3)
will be included in this safety and immune sub-cohort (Table 4). Up to 150 enrolled in 
each contributing country (if 3 contributing countries) or up to 225 subjects enrolled in 
each contributing country (if 2 contributing countries) may be included in the safety and 
immune sub-cohort.
To ensure the gender of the study population is equally distributed between females and 
males, a cap has been put on the number of subjects per gender to be enrolled. A 
maximum of 60% of subjects from the same gender will be enrolled in the study and 
enrolment of females/males will be stopped at approximately 2100 subjects of any gender 
maximum. (Amended: 29 January 2014)
Refer to section 11.3 for a detailed description of the criteria used in the determination of 
sample size.
Table 4
Sub-cohorts
Sub-cohort name
Description of additional activities
Estimated number 
of subjects
Safety and immune
sub-cohort
Safety parameters for this sub-cohort will be collected as follows:
•
Solicited AEs will be collected for 7 days (day of 
vaccination and 6 subsequent days) following vaccination.
•
Serum biochemistry/haematology values will be measured 
at Days 0, 7, 30, and 37.
Immunogenicity:
•
Humoral immunogenicity will be evaluated by measuring 
M72-specific IgGs at Days 0 and 60 and Years 1, 2 and 3.
•
CMI will be evaluated by measuring M72-specific CD4+ 
and CD8+ T cells expressing at least 2 immune markers (CD40-L 
and/or IFN-γ and/or IL-2 and/or TNF-) at Days 0 and 60 and Years
1, 2 and 3 and any combination among CD40-L, IFN-g, IL-2 and 
TNF-a. (Amended: 29 January 2014)
450
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
44
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
45
5.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the diary cards, return for follow-up 
visits).

A male or female between, and including, 18 and 50 years of age at the time of 
obtaining informed consent.

Written (or thumb printed and witnessed) informed consent obtained from the 
subject.

Baseline positive IGRA test result (Amended: 29 January 2014)

Baseline negative HIV screen. (Amended: 29 January 2014) 

Baseline negative clinical screening questionare and negative sputum sample for 
Pulmonary TB disease. (Amended: 29 January 2014)

Healthy subjects or those with chronic well-controlled disease as established by 
medical history and clinical examination.

Female subjects of non-childbearing potential may be enrolled in the study.

Non-childbearing potential is defined as pre-menarche, current tubal ligation, 
hysterectomy, ovariectomy or post-menopause *

Female subjects of childbearing potential may be enrolled in the study, if the subject:

has practiced adequate contraception* for 25 days prior to vaccination, and

has a negative pregnancy test on the day of screening and the day of first
vaccination, and

has agreed to continue adequate contraception during the entire vaccination
period and for 2 months after completion of the vaccination series.
(Amended: 29 January 2014)
*Please refer to the glossary of terms for the definitions of menarche, menopause and 
adequate contraception.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
45
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
46
5.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Current TB disease or history of TB disease and/or treatment for TB (including 
IPT). (Amended: 29 January 2014)

Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccines within 30 days preceding the first dose of study vaccine, or planned 
use during the study period.

Planned administration/administration of a vaccine not foreseen by the study protocol 
in the period starting 30 days before and ending 30 days after each dose of vaccine.

History of previous administration of experimental Mtb vaccines.

Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs within six months prior to 
the first vaccine dose. (For corticosteroids, this will mean prednisone ≥ 20 mg/day or 
equivalent.). Inhaled and topical steroids are allowed.

Any condition or illness (acute, chronic or history) or medication, which in the 
opinion of the Investigator might interfere with the evaluation of the safety or 
immunogenicity of the vaccine.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

Planned participation or participation in another experimental protocol during the 
study.

Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational product (pharmaceutical product or device).

Administration of immunoglobulins and/or any blood products within the 3 months 
preceding the first dose of study vaccine or planned administration during the study 
period.

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines.

History of medically confirmed autoimmune disease (e.g. Type I diabetes, Lupus).
(Amended: 29 January 2014)

Pregnant or lactating female.

Female planning to become pregnant or planning to discontinue contraceptive 
precautions during the vaccination period and/or before 2 months after completion of 
the vaccination series.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
46
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
47
6.
CONDUCT OF THE STUDY
6.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable subject privacy requirements and the guiding principles of 
the Declaration of Helsinki.
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written (or thumb printed and witnessed) informed consent must be 
obtained from each subject, as appropriate, prior to participation in the study.
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
47
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
48
6.2.
Subject identification and randomisation of treatment
6.2.1.
Subject identification
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study centre.
6.2.2.
Randomisation of treatment
6.2.2.1.
Randomisation of supplies
The randomisation of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centres /warehouse(s).
To allow “The Collaboration” to take advantage of greater rates of recruitment than 
anticipated at individual centres in this multi-centre study and to thus reduce the overall 
study recruitment period, an over-randomisation of supplies will be prepared. 
6.2.2.2.
Treatment allocation to the subject
6.2.2.2.1.
Study group and treatment number allocation
The target will be to enrol approximately 3506 eligible subjects who will be randomly 
assigned to two study groups in a 1:1 ratio (approximately 1753 subjects in each group).
(Amended: 29 January 2014)
Allocation of the subject to a study group at the investigator site will be performed using 
an internet based randomisation system (SBIR). The randomisation algorithm will use a 
minimisation procedure accounting for:

Centre (Amended: 29 January 2014)

Gender: a maximum of 2100 females/males will be recruited. (Amended: 29 
January 2014)
Minimisation factors will have equal weight in the minimisation algorithm.
The treatment numbers will be allocated by dose at the site of the investigator using
SBIR.
After obtaining the informed consent from the subject and having checked the eligibility 
of the subject, the site staff in charge of the vaccine administration will access SBIR. 
Upon providing the subject identification number, the randomisation system will 
determine the study group and will provide the treatment number to be used for the first
dose. The number of each administered treatment must be recorded in the eCRFon the 
Vaccine Administration screen. (Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
48
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
49
When SBIR is not available, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions.
6.2.2.2.2.
Treatment number allocation for subsequent doses
For each dose subsequent to the first dose, the study staff in charge of the vaccine
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group.
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen.
6.2.3.
Allocation of subjects to assay subsets
Approximately 450 subjects will be included in the safety and immune sub-cohort. These
subjects will be enrolled at selected centres. Blood sampling and safety assessment will 
be performed as described in Table 4. Distribution of subjects in the sub-cohort is 
presented in Table 5. (Amended: 29 January 2014)
Table 5
Distribution of subjects in the sub-cohort
Sub-cohort
Treatment group
N to be enrolled
Safety and immune sub-cohort
M72AS01
Approximately 225
Control
Approximately 225
6.3.
Method of blinding
The study will be conducted using double-blind procedures. The vaccine recipient,
investigator and any person involved in the clinical conduct of the study will be unaware 
of which vaccine was administered.
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.
6.4.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical and operational information that 
does not impact the safety of the subjects. (Amended: 29 January 2014)
6.4.1.
Surveillance for safety and efficacy
Surveillance for efficacy starts with administration of the first dose of study vaccine or 
placebo.
6.4.1.1.
Active follow-up for safety and efficacy
Subject safety follow-up and timely case capture of incident TB disease is of paramount 
importance. In addition to study visits at the study facilities, regular contacts (every two 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
49
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
50
months) with the study subjects must be maintained using one or more of the following 
methods:

Regular interval home visits by site staff.

Phone calls to inquire about current health status, completed by home visits if the 
subject cannot be reached.

1-way short message service (sms) reminders and/or 2-way sms exchange.
(Amended: 29 January 2014)
These active follow-up procedures for surveillance of safety and efficacy will be 
described in local study Standard Operating Procedures and ICFs. ICFs will be submitted 
to the Ethics Committee for approval prior to implementation.
During study visits and contacts, subjects will be asked if they have signs or symptoms of 
pulmonary TB. Based on clinical suspicion of TB, and guided by the World Health 
Organisation (WHO) signs and symptoms algorithm [WHO, 2009], they will be required 
to provide three sputum samples, preferably taken in the morning and within one week, to 
be tested for Mtb by Xpert MTB/RIF and microbiological culture.
6.4.1.2.
Passive follow-up for efficacy
Subjects will be informed about signs and symptoms compatible with TB at the time of 
Informed Consent and at each visit/contact. At any time during the study, if a subject 
suspects that he/she has signs and symptoms of TB, he/she will be required to self-report
to the study centre for clinical evaluation (passive follow-up) and if needed confirmatory 
testing using Xpert MTB/RIF and microbiological culture will be done.
6.4.2.
Diagnostic procedures for the detection of suspected pulmonary 
TB
During the entire study period, when a subject presents with clinical suspicion of 
pulmonary TB, three respiratory sputum samples, preferably taken in the morning, must 
be collected, within a one week interval, for testing with Xpert MTB/RIF and 
microbiological culture. If results are negative but clinical suspicion of TB disease 
persists, the subject will be cared for according to local clinical practice (e.g. treated with 
non anti-tuberculosis antibiotics) and will be followed up approximately two weeks later. 
If clinical suspicion persists, three additional sputum samples, preferably taken in the 
morning, within a one week interval, will be collected for Xpert MTB/RIF testing and 
microbiological culture. If TB disease cannot be confirmed with Xpert MTB/RIF and/or 
microbiological culture, the subject may be given TB treatment based on other diagnostic 
tests (e.g. smear microscopy) and the judgement of the physician providing care.
Weight of the subject must also be recorded in the subjects’ eCRF at the time of TB 
diagnosis.
Protocol samples for diagnostic testing with Xpert MTB/Rif and/or microbiological 
culture should preferably be taken before initiation of TB treatment. However, samples 
for diagnostic testing with Xpert MTB/Rif and/or microbiological culture may be 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
50
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
51
collected up to four weeks after initiation of TB treatment. Definite Pulmonary TB cases
identified from sputum samples taken after initiation of TB treatment will not be included 
in the primary endpoint.
Testing results per protocol procedures will be communicated expeditiously to the 
investigator but their availability should not delay any diagnostic or therapeutic 
intervention as per local routine practice.
Additionally if TB is confirmed a serological test (and pre-test counselling) for HIV-
infection must be performed to rule out HIV co-infection. If the subject is HIV-positive, 
additional testing must be performed to measure CD4 cell counts. Diabetes will be 
screened for by a Hb Ac1 test. (Amended: 29 January 2014)
Results of HIV testing, including CD4 cell counts if applicable must be recorded in the 
subjects’ eCRF. (Amended: 29 January 2014)
6.4.3.
Diagnostic procedures for suspected extra-pulmonary TB
During the entire study period, when a subject presents with clinical suspicion of extra-
pulmonary TB, a diagnostic procedure must be performed according to local clinical 
practice and as a minimum, the most recent WHO recommendations in the “International 
Standards for TB care” should be followed [WHO, 2006].
The diagnostic procedures performed and their results must be recorded in the subjects’
eCRF along with the final diagnosis of the attending physician.
Additionally, if extra-pulmonary TB is confirmed, a serological test (and pre-test & post-
test counselling) for HIV-infection must be performed to rule out HIV co-infection must 
be taken. If the subject is HIV-positive, additional testing must be performed to measure
CD4 cell counts. Diabetes will be screened for by a Hb Ac1 test. (Amended: 29 January 
2014)
Results of HIV testing, including CD4 cell counts, if applicable must be recorded in the 
subjects’ eCRF. (Amended: 29 January 2014)
6.4.4.
Procedures for fatalities
In order to diagnose the cause of death of fatalities occurring during this study, it is 
recommended that a verbal autopsy (VA) will be performed by the study staff for all 
fatalities, using a standardised VA questionnaire and cause of death qualification [WHO, 
2007].
Verbal Autopsy reports that are shared with the collaboration or any vendors acting on 
behalf of the collaboration must be anonymised, i.e. all personally identifiable 
information should be removed. In the event that this occurs a GSK data privacy breach 
form will need to be completed. (Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
51
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
52
6.4.5.
Safety Monitoring Plan
6.4.5.1.
Safety Review Team
The Safety Review Team (SRT) includes as core members the GSK Biologicals’ Central 
Safety Physician, the Clinical Development Manager, Epidemiologist, Clinical 
Regulatory Affairs representative and the Biostatistician of the project. The SRT will be 
responsible for ongoing safety monitoring of the study and will meet on a regular basis.
In order to keep all people involved in the conduct, cleaning and final analysis of the 
study blinded, the SRT will monitor safety in a blinded manner.
6.4.5.2.
Independent Data Monitoring Committee
In order to ensure the safety of the subjects during the entire study period, an Independent 
Data Monitoring Committee (IDMC) has been appointed to monitor the safety and 
tolerability of the vaccine/placebo administered in the trial and, if necessary, make 
recommendations to the sponsor concerning the modification or termination of the trial.
The IDMC will perform safety reviews twice a year or more frequently if deemed 
necessary on an ongoing basis during the study period. (Amended: 29 January 2014)
An independent statistical team (i.e., comprising members who are neither GSK 
employees neither Aeras employees and who are not involved in the study management) 
will be appointed by GSK Biologicals. This team will be unblinded to treatment 
assignment and provide all necessary tables, listings, figures and individual subject data 
to the IDMC.
The IDMC consists of clinical experts who are not involved in the conduct of the study 
and an independent statistician. The role of the IDMC will be to review the progress of 
the trial and safety assessments to detect evidence of safety issues for the subjects from 
the time of first vaccination and throughout the duration of the trial. A report, with 
recommendations as necessary, will be provided to the sponsor following each IDMC 
meeting. The frequency of IDMC sessions and other operational details are described in 
the IDMC charter. In case of a serious safety issue during the study, the sponsor will 
inform the IDMC as well as fulfil its regulatory obligation expeditiously. (Amended: 29 
January 2014)
If during the course of enrolment and vaccination two or more related grade 2 or 3 
respiratory AE are observed an ad hoc IDMC will be convened. (Amended: 29 
January 2014)
6.4.5.3.
Planned safety review (Amended: 29 January 2014)
A planned safety review after the first 100 subjects have been enrolled and vaccinated 
will be performed. The SRT will review blinded safety summaries and the IDMC will 
review unblinded safety summaries.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
52
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
53
6.4.5.4.
Rules for vaccination (Amended: 29 January 2014)
At individual subject level

No second dose should be administered in a given subject who experiences Grade 
3 redness and swelling, i.e. 100mm, post dose 1 or Grade 2 or 3 respiratory AE 
post dose 1.

No second dose should be administered in a given subject who develops TB disease 
after dose 1. 
At study level

An ad hoc IDMC review will be called if 2 or more subjects experience related 
Grade 2 or higher respiratory AEs within 90 days after any dose.

Further enrolment and vaccination will be suspended if within 90 days after any 
study vaccine dose any of the following events are observed:

Related respiratory AE with Fatal outcome

Two or more subjects experiencing Grade 3 related Respiratory AE

An ad hoc IDMC meeting will be called urgently for review. Vaccination may only 
be allowed to resume pending final VSMB approval.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
53
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
54
Table 6
Safety holding rules for vaccination (Amended: 29 January 2014)
Event
Grade
Occurrences
Action for 
subject(s)
Trial actions
Redness/Swelling 
at injection site
(within 30 days after 
dose 1)
Grade 3
(>100mm)
any 
subject(s)
No dose 2 in same 
subject(s), 
keep in efficacy 
follow-up
-
TB disease (after dose 
1)
n/a
Any 
subject(s)
No dose 2 in same 
subject(s) , 
keep in efficacy 
follow-up
-
Respiratory SOC AE
(within 90 days after 
dose 1)
Grade ≥2
1 subject
No dose 2 in same 
subject(s),
but keep in 
efficacy follow-up
Clinical 
assessment & 
further 
investigation at 
investigator 
discretion
-
Respiratory SOC AE
(within 90 days after
dose 1)
Grade ≥2 
related
≥2 subjects
Ad hoc
IDMC 
review
Respiratory SOC SAE
Related & 
Fatal
≥1 subject
-
Study Hold,
IMDC 
Review,
VSMB
Respiratory SOC AE
(within 90 days after
dose 1)
Grade ≥3, 
related
≥2 subjects
No dose 2 in same 
subject(s)
Clinical 
assessment & 
further 
investigation at 
investigator 
discretion
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
54
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
55
6.5.
Outline of study procedures
Table 7
List of study procedures (Amended: 29 January 2014)
Visit 1 Screening 
visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 6
Contact 1, 
2, 3 and 4
Visit 7
Contact 5, 
6, 7, 8, 9
Visit 8
Contact 10, 
11, 12, 13, 14
Visit 9
Time point(s)
D-30 to D0
D 0
D 7
D 30
D 37
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
All subjects 
Informed consent
●
Check inclusion/exclusion 
criteria
●
●
Collect demographic data
●
Medical history
●
●
Physical examination
●
History-directed physical 
examination
O
O
O
O
O
Resting vital signs
O
O
HIV testing2 (up to 2.5 
mL/test) 
●
●
Record weight3
●
●
●
●
Documentation of history 
of BCG 
vaccination/presence of 
scar
●
Visit 1
Documentation of history 
of TB household contacts
●
Pregnancy test (-HCG 
urine)
●
●
●
Study group and treatment 
number allocation for first 
dose
O
Treatment number 
allocation for second dose
O
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
55
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
56
Visit 1 Screening 
visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 6
Contact 1, 
2, 3 and 4
Visit 7
Contact 5, 
6, 7, 8, 9
Visit 8
Contact 10, 
11, 12, 13, 14
Visit 9
Time point(s)
D-30 to D0
D 0
D 7
D 30
D 37
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Vaccination
●
●
Recording of administered 
treatment number
●
●
Check contraindications to 
subsequent vaccination
●
●
Recording concomitant 
medication/vaccination
●
●
●
●
●
●
●
●
●
●
●
Recording intercurrent 
medical condition
●
●
●
●
●
●
●
●
●
●
●
Distribution of diary cards
O
O
Return of diary cards
O
O
Recording of unsolicited 
AEs and large swelling 
reactions
●
●
●
●
●
Pre-vaccination 
assessment (including 
temperature)
●
●
Blood sampling for QFTG
(3 mL)
●
Sputum collection for 
Xpert testing
●
Reporting SAEs
●4
●
●
●
●
●
●5
●4
●4
●4
●4
●4
Reporting pIMDs
●
●
●
●
●
●6
Reporting pregnancy
●
●
●
●
●
●6
Diagnostic procedures for 
suspected pulmonary TB7
●
●
●
●
●
●
●
●
●
●
Documentation of TB 
cases8
●
●
●
●
●
●
●
●
●
●
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
56
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
57
Visit 1 Screening 
visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 6
Contact 1, 
2, 3 and 4
Visit 7
Contact 5, 
6, 7, 8, 9
Visit 8
Contact 10, 
11, 12, 13, 14
Visit 9
Time point(s)
D-30 to D0
D 0
D 7
D 30
D 37
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Safety and immune sub-
cohort
Measuring Vitamin D
●
Recording of solicited AEs
●
●
●
●
CBC (Hb, PLT and WBC), 
ALT, AST, creatinine, 
bilirubin (8 mL)
●
●
●
●
Blood sampling for Wh.Bl.
CMI (2.5 mL)
●
●
●
●
●
Blood sampling for 
humoral immunogenicity (
2 mL)
●
●
●
●
●
Study conclusions for all 
subjects
●
Note: The double border at Month 36 indicates the final analyses which will be performed on all data obtained up to month 36.
Pre V: Pre Vaccination; V: Vaccination; Post V: Post Vaccination
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
1 Only subjects in the safety and immune sub-cohort need to come for this visit.
2 HIV testing, pre-test and post-test counselling will be performed whenever a HIV test is done, according to the procedures detailed in Table 10.
3 Weight also needs to be recorded whenever there is suspicion of TB disease.
4 Only SAEs related to study participation or concurrent GSK medication/vaccine.
5 SAEs not related to study participation or concurrent GSK medication/vaccines will be recorded until 6 months post dose 2 (M7).
6 To be recorded until 6 months post dose 2 (M7).
7 Sputum samples for Xpert MTB/RIF testing and microbiological culture will be taken throughout the study if a subject presents with clinical suspicion of pulmonary TB disease. Three 
sputum samples, preferably taken in the morning and within max. one week, must be collected. Additionally, when a subject is diagnosed with TB, screening for diabetes (HbA1C) 
and HIV testing must be performed according to the procedures detailed in Table 10. Up to 2.5mL of blood will be collected per test. If the subject is confirmed HIV-positive, blood 
samples must be taken (2.5 mL) to measure CD4 counts.
8 Documentation of TB cases will be done throughout the study, starting at Visit 3 (Day 7); this includes documentation of cases during active and passive follow-up and monitoring of 
medical facilities and pharmacies.
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
57
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
58
Table 8
Intervals between study visits for all subjects (Amended: 29 January 
2014)
Interval
Allowed interval1
Visit 1 - Visit 2
0 days - 30 days
Visit 2 - Visit 4
26 days - 35 days
Visit 4 - Visit 6
26 days - 35 days
Visit 4 -Visit 7
10 months - 12 months
Visit 4 - Visit 8
22 months -24 months
Visit 4 - Visit 9
34 months - 36 months
Visit n – next contact
6 weeks – 12 weeks
Contact n – contact n+1
6 weeks – 12 weeks
1 Subjects may not be eligible for inclusion in the ATP cohort for analysis of immunogenicity and efficacy if they attend 
for a study visit outside this interval.
Table 9
Intervals between study visits specific for the safety and immune 
sub-cohort
Interval
Allowed interval1
Visit 2 - Visit 3
6 days - 10 days
Visit 4 - Visit 5
6 days - 10 days
1 Subjects may not be eligible for inclusion in the ATP cohort for analysis of immunogenicity and efficacy if they make 
the study visit outside this interval.
6.6.
Detailed description of study procedures
6.6.1.
Informed consent
The signed/witnessed/thumb printed informed consent of the subject must be obtained 
before study participation. Refer to Section 6.1 for the requirements on how to obtain 
informed consent as appropriate. Consenting and screening may be repeated, but only 
once, for subjects who would return out of screening interval but still agree to participate. 
6.6.2.
Check inclusion and exclusion criteria
Check all inclusion and exclusion criteria as described in Sections 5.2 and 5.3 before 
enrolment.
6.6.3.
Collect demographic data
Record demographic data such as date of birth, gender and ethnicity in the subject’s 
eCRF.
6.6.4.
Collect history of TB household contacts
Question the subject about recent exposure (within the last 12 months) to a person 
(household contact) diagnosed with and/or treated for pulmonary TB disease.
Record history of TB household contacts in the subject’s eCRF.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
58
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
59
6.6.5.
Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF. In particular, chronic pulmonary 
conditions (such as COPD, silicosis), history of smoking and diabetes* must be recorded
(* type I diabetes is an exclusion criterion). (Amended: 29 January 2014)
6.6.6.
Physical examination 
Perform a physical examination of the subject at screening, including assessment of body 
temperature, height, weight and resting vital signs: systolic/diastolic blood pressure, heart 
rate and respiratory rate after at least 10 minutes of rest. Height and weight of the subject 
need to be recorded in the eCRF. (Amended: 29 January 2014)
Physical examination at each study visit subsequent to the screening visit, will be 
performed only if the subject indicates during questioning that there might be some 
underlying pathology(ies) or if deemed necessary by the Investigator or delegate.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
6.6.7.
History directed physical examination 
Perform a history directed physical examination. If the investigator determines that the 
subject’s health on the day of vaccination temporarily precludes vaccination, the visit will 
be rescheduled within the window period (Table 8). (Amended: 29 January 2014)
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
6.6.8.
Urine pregnancy test 
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine administration. The study vaccine/placebo may only be administered if the 
pregnancy test is negative. Additionally, a urine pregnancy test will be performed at 
screening.
Note: The urine pregnancy test must be performed even if the subject is menstruating at 
the time of the study visit.
6.6.9.
Check contraindications to vaccination
Contraindications to vaccination must be checked at the beginning of each vaccination 
visit. Refer to Section 7.5 for more details.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
59
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
60
6.6.10.
Assess pre-vaccination body temperature
The axillary, oral or tympanic body temperature of all subjects needs to be measured 
prior to any study vaccine administration. The preferred route for recording temperature 
in this study will be axillary. If the subject has fever [fever is defined as temperature 
37.5°C/99.5°F for oral, axillary or tympanic route] on the day of vaccination, the 
vaccination visit will be rescheduled within the allowed interval for this visit (see Table 
8). (Amended: 29 January 2014)
6.6.11.
Study group and treatment number allocation
Study group and treatment number allocation will be performed as described in Section 
6.2.2. The number of each administered treatment must be recorded in the eCRF.
6.6.12.
Sampling
6.6.12.1.
Blood sampling for safety and immune response assessments
(Amended: 29 January 2014)
As specified in the List of Study Procedures in Section 6.5 (Table 7), blood samples are 
taken during certain study visits. Refer to the Module on Biospecimen Management in 
the SPM and lab manual for detailed instructions for the collection, handling and 
processing of the samples.

For all subjects:

At screening, HIV testing must be performed according to the procedures 
detailed in Table 10. Up to approximately 2.5 mL of blood will be collected for 
each test.

A volume of at least 3 mL of whole blood must be drawn for QFTG testing at 
screening (Table 10)
(Amended: 29 January 2014)

For all subjects included in the safety and immune sub-cohort:

A volume of at least 2 mL of whole blood should be drawn for analysis of 
humoral immune responses at each predefined time point (Table 10).

A volume of at least 2.5 mL of whole blood should be drawn for analysis of cell-
mediated immune (CMI) responses at each predefined time point (Table 10).

A volume of at least 8 mL of whole blood should be drawn for tests performed to 
assay for CBC, ALT, AST, bilirubin and creatinine at each predefined time point
(Table 10). Vitamin D levels will be measured at Day 0 only.
(Amended: 29 January 2014)

Whenever a subject is diagnosed with TB disease:

Screening for diabetes and HIV testing must be performed according to the 
procedures detailed in Table 10. Up to approximately 2.5 mL of blood will be 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
60
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
61
collected for each test. Additionally, if HIV is confirmed, at least 2.5 mL of 
blood will be collected to measure CD4 counts. (Amended: 29 January 2014)
6.6.12.2.
Sputum sample collection for TB screening (Amended: 29 January 
2014)
A single sputum sample must be collected from all subjects going through screening 
for testing using Xpert. 
6.6.12.3.
Sputum sample collection for TB diagnosis
Subjects suspected with Pulmonary TB will be required to provide 3 sputum samples, 
preferably taken in the morning, within maximum a one week interval, of preferably up 
to 5 mL to test for Mtb using the Xpert MTB/RIF assay and microbiological culture 
whenever the subject presents with clinical suspicion of pulmonary TB. If needed, 
induction of sputum through nebulisation of hypertonic saline may be performed.
(Amended: 29 January 2014)
Refer to the Module on Biospecimen Management in the SPM and lab manual for 
detailed instructions for the induction of sputum, collection, handling and processing of 
the samples.
6.6.13.
TB disease capture
During active follow-up at regular visits/contacts, the subjects will be questioned for the 
presence of signs and symptoms of pulmonary TB disease and assessed for clinical 
suspicion of pulmonary TB disease.
During passive follow-up (i.e. if a subject recognises signs and symptoms of TB and self-
reports), the subjects will be assessed for clinical suspicion of pulmonary TB disease.
If clinical suspicion of pulmonary TB disease exists, diagnostic procedures per protocol 
will be performed (refer to Section 6.4.2).
If clinical suspicion of extra-pulmonary TB disease exists, diagnostic procedures 
according to local clinical practice will be performed (refer to Section 6.4.3).
At each visit or contact, the subject will be asked if he/she has sought care or received 
treatment for tuberculosis or suspicion of tuberculosis. Such TB cases fall under the fifth
case definition and will be recorded as clinical TB.
Additionally, medical facilities and Pharmacists awareness (if applicable) and 
surveillance will be put in place in the study area to ensure that TB disease cases 
occurring in study participants are captured. All Medical facilities and Pharmacists in the 
study area will be informed of the trial. A team of study personnel/health workers will 
visit the medical facilities monthly to identify study subjects admitted to or cared for at 
the hospitals for TB. Relevant staff at the medical facilities will be advised to contact the 
study personnel for each TB case to ensure that all cases are captured.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
61
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
62
6.6.14.
Study Vaccine administration

After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine/placebo will be administered intramuscularly (IM) in the deltoid of the arm 
(refer to Section 7.3 for detailed description of the vaccine administration 
procedure). If the investigator or delegate determines that the subject’s health on the 
day of administration temporarily precludes vaccine administration, the visit will be 
rescheduled within the allowed interval for this visit (refer to Table 8).

The subjects will be observed closely for at least 30 minutes following the 
administration of the vaccine, with appropriate medical treatment readily available in 
case of anaphylaxis.
6.6.15.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 7.6.
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 7.7.
Recording of AEs, SAEs, pregnancies and pIMDs

Refer to Section 9.2 for procedures for the investigator to record AEs, SAEs, 
pregnancies and pIMDs. Refer to Section 9.3 for guidelines on how to submit SAE, 
pregnancy and pIMD reports to GSK Biologicals.

The subjects will be instructed to contact the investigator immediately should they
manifest any signs or symptoms they perceive as serious.

At each vaccination visit, diary cards will be provided to the subjects. Any 
unsolicited AEs (i.e. on the day of vaccination and during the next 29 days) 
occurring after vaccination will be recorded by all subjects. The subjects included in 
the safety and immune sub-cohort will also record body (axillary) temperature and 
any solicited local/general AEs (i.e. on the day of vaccination and during the next 6 
days). In case of illiterate subjects, a designated person (such as a family member or 
a field worker) may provide assistance to complete the diary cards. The subject will 
be instructed to return the completed diary card to the investigator at a later visit. In 
case a diary card is lost by the subject or he/she is unable to complete the diary card, 
the safety information should be captured retrospectively using a descriptive 
interview. The site staff or Investigator should not write on the diary card, this 
information should be captured in the source notes. This process will be 
documented in a site SOP. Please refer to the SPM for further details. (Amended: 29 
January 2014)

Verify completed diary cards during discussion with the subject on Visits 2, 3*, 4, 5* 
and 6. Collect diary cards from the subjects at Visits 4 and 6. Any unreturned diary 
cards will be sought from the subject through telephone call(s) or any other 
convenient procedure. The investigator will transcribe the collected information into
Inform™in English. *Only for subjects included in the safety and immune sub-
cohort. (Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
62
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
63
6.6.16.
Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness.

complete the Study Conclusion screen in Inform™. (Amended:29 January 2014)
After study conclusion, if vaccine efficacy is demonstrated, recipients of the placebo will 
be offered the vaccine candidate.
6.7.
Biological sample handling and analysis
Please refer to the SPM and lab manual for details on biospecimen management 
(handling, storage and shipment).
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number).
Under the following circumstances, additional testing on the samples may be performed 
by GSK Biologicals, by laboratories working for GSK Biologicals, by laboratories 
working in collaboration with GSK and by laboratories involved in studies ancillary to 
TB-018, outside the scope of this protocol (Amended: 29 January 2014):

Collected samples may be used in other assays, for test improvement or development 
of analytical methods related to the study vaccines and its constituents or the disease 
under study.

Collected samples may be used for purposes related to the quality assurance of data 
generated linked to the study vaccines or the disease under study, such as for
maintenance of assays described in this protocol and comparison between analytical 
methods and/or laboratories.
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.
Any sample testing will be done in line with the consent of the individual subject.
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
63
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
64
6.7.1.
Use of specified study materials
When materials are provided by “The Collaboration”, it is MANDATORY that all 
clinical samples (including serum samples) be collected and stored exclusively using 
those materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analysis (See Section 11.4 for the definition of 
study cohorts/ data sets to be analysed). The investigator must ensure that his/her 
personnel and the laboratory(ies) under his/her supervision comply with this requirement. 
However, when “The Collaboration” does not provide material for collecting and storing 
clinical samples, appropriate materials from the investigator’s site must be used. Refer to 
the Module on Clinical Trial Supplies in the SPM and lab manual.
6.7.2.
Biological samples
6.7.2.1.
Protocol mandated testing and enpoints (Amended: 29 January 2014)
Table 10
Biological samples (Amended: 29 January 2014)
Sample type
Quantity
Unit
Time point
Subjects
Blood sampling for Safety 
assessment
At least 8
ml
Days 0, 7, 30 and 371
Safety and immune 
sub-cohort2
Blood sampling for 
Humoral responses
At least 2
ml
Days 0, 60 and Years 1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for CMI
At least 2.5
ml
Days 0, 60 and Years 1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for QFTG
At least 3
ml
At screening
All subjects
Sputum sampling for 
TB screening
Up to 5
ml
At Screening
All subjects
Sputum sampling for TB 
diagnosis3
Approximately 5
ml
Throughout the study when 
pulmonary TB is suspected
All subjects with 
suspicion of 
pulmonary TB
Blood sampling for initial 
HIV testing - Step 1 
(Rapid test)
Finger prick or at 
least 2.5
ml
At screening, 
At Visit 9 (study end)
All subjects
When TB diagnosis is confirmed
All subjects 
diagnosed with TB
Blood sample for HIV 
testing - Step 2 (Rapid 
test)
Finger prick or at 
least 2.5
ml
At screening and when TB 
diagnosis is confirmed
All subjects positive 
at Step 14
Blood sampling for HIV 
testing - Step 3 (ELISA)
At least 2.5
ml
At screening, 
At Visit 9 (study end)
Discordant Rapid 
test results or if no 
Rapid test 
performed5
When TB diagnosis is confirmed
Blood sampling for PCR -
Step 4
At least 2.5
ml
When TB diagnosis is confirmed
Indeterminate ELISA 
results5
Blood sampling for CD4 
count
At least 2.5
ml
When TB diagnosis is confirmed 
and confirmed HIV-positive
HIV positive 
subjects with TB 
diagnosis confirmed
Blood sampling for 
HbA1C
At least 2.5
ml
When TB diagnosis is 
confirmed
Subjects with TB 
diagnosis 
confirmed
1 Vitamin D levels will be measured at day 0 only.
2 Refer to Section 5.1 for sub-cohort description.
3 Three sputum samples, preferably taken in the morning, within a one week interval, will be collected whenever a 
subject presents with clinical suspicion of pulmonary TB.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
64
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
65
4 HIV positive subjects at screening will be referred for confirmatory HIV diagnosis/management as per site SOPs.
5 Only the final conclusive diagnosis is to be recorded in the CRF.
6.7.3.
Laboratory assays
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories used for 
sample analysis.
The main laboratory assays will be performed at GSK Biologicals’ laboratory or in a 
laboratory designated by “The Collaboration” using standardised and/or qualified 
procedures (Table 11 - Table 15).
Table 11
Humoral Immunity (Antibody determination)
System
Component
Method
Kit/Manufacturer
Unit
Cut-off
Laboratory*
Serum
Mycobacterium 
tuberculosis.M72 
Ab.IgG
Enzyme 
Linked 
Immuno 
Sorbent 
Assay
NA
enzyme linked 
immunosorbent 
assay unit per 
milliliter
2.8
CEVAC**
*Refer to APPENDIX B for the laboratory addresses.
**Or as designated by GSK Biologicals.
Table 12
Cell-Mediated Immunity (CMI) (Amended: 29 January 2014)
System
Component
Challenge
Method
Unit
Cut-off
Laboratory*
Whole 
blood
CD4+/CD8+ T cells expressing at 
least two immune markers 
(CD40L and/or IL-2 and/or TNF-
and/or IFN-) and any 
combination among CD40-L, 
IFN-g, IL-2 and TNF-a
M72
ICS -
intraCellular 
Cytokine 
Staining 
number of 
events per 
million cells 
N/A 
GSK or as 
designated 
by GSK
*Refer to APPENDIX B for the laboratory addresses.
Table 13
Diagnostic tests for pulmonary TB disease (Amended: 29 January 
2014)
System
Component
Method
Unit
Laboratory*
Component 
priority ranking
Sputum
Mycobacterium 
tuberculosis DNA
Xpert MTB/RIF 
assay
NA
Central Laboratory
1
Sputum
Mycobacterium 
tuberculosis
Microbiological 
culture
NA
Central Laboratory
2
Sputum
Mtb
Strain Typing
NA
Central lab
3
*Refer to APPENDIX B for the laboratory addresses.
In case of insufficient sputum sample volume to perform both Xpert MTB/RIF and 
microbiological culture, the samples will be analysed according to priority ranking 
provided in Table 13.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
65
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
66
Table 14
Diagnostic tests for HIV (Amended: 29 January 2014)
System
Component
Method
Unit
Laboratory*
Whole Blood or Serum
Anti-HIV antibodies, 
screening step 1, step 2
HIV Rapid Test**
NA
At the Investigator’s 
lab
Serum
Anti-HIV antibodies,
screening step 3
ELISA
NA
At the Central 
Laboratory
Whole Blood
HIV
screening step 4
HIV PCR
NA
At the Central 
Laboratory
Whole blood
CD4 cells
Flow cytometry
Cells/mm3
At the Central 
Laboratory
*Refer to APPENDIX B for the laboratory addresses.
**Two different Rapid HIV tests to be used sequentially
Table 15
Haematology, Serum Chemistry, Urine tests
System
Component
Method
Scale
Whole blood
Alanine amino transferase
As per laboratory
standard procedures
Quantitative
Aspartate amino transferase
Creatinine
Bilirubin (total)
Platelets
Leucocytes
Erythrocytes
Haemoglobin
Vitamin D
IFN-release by T-cells
QuantiFERON® TB 
Gold Assay
Quantitative
Urine
-HCG
As per laboratory 
standard procedures
Qualitative
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department.
6.7.4.
Biological samples evaluation per protocol (Amended: 29 
January 2014)
6.7.4.1.
Diagnostic assays
Xpert MTB/RIF testing (Cepheid) and microbiological culture will be performed on three 
sputum samples, preferably taken in the morning, within a maximum one week interval,
for all subjects presenting with clinical suspicion of pulmonary TB throughout the entire 
study. (Amended: 29 January 2014)
HIV testing and pre-test and post-test counselling will be performed at screening. HIV 
positive subjects at screening will be referred for confirmatory HIV 
diagnosis/management as per site SOPs and won’t be enrolled (exclusion criterion). 
(Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
66
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
67
Whenever a subject is diagnosed with TB disease, an HIV test (and pre-test counselling)
must be performed to rule out HIV co-infection. HbA1c measurement will also be 
performed. If a subject is diagnosed with HIV, additional tests to measure CD4 cell 
counts will be performed. Subjects with a positive test result will be referred for HIV 
treatment. (Amended: 29 January 2014)
All diagnostic assays will be carried out at the designated central laboratory as
designated by “The Collaboration”. (Amended: 29 January 2014)
6.7.4.2.
Immunological read-outs
Blood will be collected at specific time points to assay for immunological readouts. Table 
16 details the main immunological read-outs.
After collection, whole blood samples will be incubated with pool(s) of overlapping 
peptides covering the M72 antigen sequence and with the stimulation controls for 2 hours 
in the presence of anti-CD28 and anti-CD49d antibodies. Subsequently, flow cytometry 
using a short-term stimulation Intracellular Cytokine Staining (ICS) assay will be used to 
characterise M72-specific CD4+/CD8+ T cells expressing at least two immune markers
or any combination of markers, i.e. single, double, triple, quadruple, (CD40L and/or 
IL-2 and/or TNF-and/or IFN-) on Days 0, 60, and Years 1, 2 and 3. (Amended: 29 
January 2014)
The humoral immune response will be evaluated by assessment of antibody titres to M72 
by specific ELISA on Days 0 and 60, and Years 1, 2 and 3.
Table 16
Immunological read-outs (Amended: 29 January 2014) 
Blood sampling time point
Sub-cohort 
Name
No. 
subjects
Component
Type of contact 
and time point
Sampling time 
point
Visit 2 (Day 0)
Pre Vacc
Safety and 
immune sub-
cohort
450
M72-specific T-cells (ICS on whole blood)
Anti M72 Ab (ELISA on serum)
Visit 6 (Day 60)
Post Vacc 2
M72-specific T-cells (ICS on whole blood)
Anti M72 Ab (ELISA on serum)
Visit 7 (Year 1)
LTFU
M72-specific T-cells (ICS on whole blood)
Anti M72 Ab (ELISA on serum)
Visit 8 (Year 2)
LTFU
M72-specific T-cells (ICS on whole blood)
Anti M72 Ab (ELISA on serum)
Visit 9 ( Year 3)
LTFU
M72-specific T-cells (ICS on whole blood)
Anti M72 Ab (ELISA on serum)
Vacc: Vaccination
LTFU: Long Term Follow-up
6.7.4.3.
Haematology/Biochemistry
A urine pregnancy test will be performed on all female subjects at screening and prior to 
each vaccination. Urine pregnancy tests may be performed by clinical staff on the 
premises of the clinic/out-patient facility. The results of the pregnancy test must be 
recorded in the subjects’ eCRF.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
67
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
68
Serum biochemistry and haematology tests (Hb, PLT, WBC, ALT, AST, bilirubin, 
creatinine) will be performed in the safety and immune sub-cohort on Days 0, 7, 30 and 
37. To characterise the study population, vitamin D levels will be measured at baseline in 
the sub-cohort. The tests will be performed at the laboratory of the investigator’s site or 
in a laboratory designated by “The Collaboration”. Results for WBCs, haemoglobin, 
creatinine, ALT, AST, total bilirubin and vitamin D will be recorded in the subject’s 
eCRF or transferred directly to the clinical database. Table 17 details the biochemistry/ 
haematology readouts.
Table 17
Biochemistry/haematology readouts
Blood sampling time point
Sub-cohort Name
No. subjects
Component
Type of contact and 
timepoint
Sampling 
timepoint
Visit 2 (Day 0)
Pre-Vacc
Safety and immune sub-cohort
450
Hb, PLT, WBC
ALT
AST
Creatinine
Bilirubin (total)
Vitamin D
Visit 3 (Day 7)
Post-Vacc 1
Safety and immune sub-cohort
450
Hb, PLT, WBC
ALT
AST
Creatinine
Bilirubin (total)
Visit 4 (Day 30)
Post-Vacc 1
Safety and immune sub-cohort
450
Hb, PLT, WBC
ALT
AST
Creatinine
Bilirubin (total)
Visit 5 (Day 37)
Post Vacc 2
Safety and immune sub-cohort
450
Hb, PLT, WBC
ALT
AST
Creatinine
Bilirubin (total)
Vacc: Vaccination
6.7.5.
Immunological correlates of protection
No immunological correlate of protection has been demonstrated so far for the antigen(s) 
used in the candidate vaccine and/or licensed vaccines (BCG).
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
68
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
69
7.
STUDY VACCINES AND ADMINISTRATION
7.1.
Description of study vaccines
The candidate vaccine and placebo to be used have been developed and manufactured by 
GSK Biologicals.
The Quality Control Standards and Requirements for the candidate vaccine are described 
in separate Quality Assurance documents (e.g. release protocols, certificate of analysis) 
and the required approvals have been obtained.
The vaccines are labelled and packed according to applicable regulatory requirements.
Table 18
Study vaccines
Treatment 
name
Vaccine/product
name
Formulation
Presentation
Volume to be 
administered
Number 
of doses
M72/AS01E
M72
M72 (10 µg); sucrose; 
polysorbate; TRIS
Lyophilised 
cake in vial
0.5 ml
2
AS01E
25µg MPL, 25 µg QS21 in a 
liposome-based formulation
Liquid in vial
Placebo
Placebo pellet
5 % Sucrose in phosphate 
buffer
Lyophilised 
cake in vial
0.5 ml
2
Placebo adjuvant
23.8 µg -Tocopherol, 
21.4 µg squalene and 9.7 µg 
Tween 80
Liquid in vial
7.2.
Storage and handling of study vaccines
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorized 
study personnel. The storage conditions will be assessed during pre-study activities under 
the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccines.
Temperature excursions must be reported in degree Celsius.
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C/+36 to 
+46°F label storage condition) impacting investigational medicinal products (IMPs) must 
be reported in the appropriate (electronic) temperature excursion decision form (eTDF). 
The impacted IMPs must not be used and must be stored in quarantine at label 
temperature conditions until usage approval has been obtained from the sponsor.
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to 
+8°C/+36 to +46°F label storage temperature conditions. The impacted IMP(s) may still 
be administered, but the site should avoid re-occurrence of such temperature excursion.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
69
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
70
Refer to the Module on Clinical Trial Supplies in the SPM for more details on actions to 
take.
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines.
7.3.
Dosage and administration of study vaccines
Subjects will be administered the candidate vaccine M72/AS01E or placebo according to 
their random assignment:

Subjects randomised to receive M72/AS01E will be administered two doses of 
M72/AS01E according to a 0, 1 month schedule (Day 0 and Day 30).

Subjects randomised to receive the placebo will be administered two doses of 
placebo according to a 0, 1 month schedule (Day 0 and Day 30).
Each dose will be administered intramuscularly in the deltoid region of the arm.
Table 19 summarises the dosage and administration of study vaccine and placebo.
Table 19
Dosage and administration
Type of contact 
and time point
Volume to be 
administered
Study group
Treatment name
Route
Site
Side
Visit 2 (day 0)
0.5ml
0.5ml
M72AS01
M72/AS01E
IM
Deltoid
NA
Control
Placebo
IM
Deltoid
NA
Visit 4 (Day 30)
0.5ml
0.5ml
M72AS01
M72/AS01E
IM
Deltoid
NA
Control
Placebo
IM
Deltoid
NA
IM: Intramuscular
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions for 
reconstitution of M72 antigen/Placebo pellet with AS01E Adjuvant System/Placebo 
adjuvant and administration of the reconstituted study vaccines.
7.4.
Replacement of unusable vaccine doses
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 5% additional vaccine doses will be 
supplied to replace those that are unusable.
The investigator will use SBIR to obtain the replacement vial number. The replacement 
numbers will be allocated by dose. The system will ensure, in a blinded manner, that the 
replacement vial matches the formulation the subject was assigned to by randomisation.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
70
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
71
7.5.
Contraindications to subsequent vaccination
The following events constitute absolute contraindications to further administration of 
M72/AS01E. If any of these events occur during the study, the subject must not receive 
additional doses of vaccine but may continue other study procedures at the discretion of 
the investigator (see Section 9.4).

Anaphylaxis following the administration of vaccine(s).

Pregnancy (see Section 9.1.6).

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including HIV-infection.

Active TB disease.

Grade 3 local symptoms redness and swelling, i.e. >100mm or Grade ≥2 
respiratory AE following the administration of vaccine(s). (Amended: 29 January 
2014).
The following events constitute contraindications to administration of M72/AS01E at that 
point in time; if any of these events occur at the time scheduled for vaccination, the 
subject may be vaccinated at a later date, within the time window specified in the 
protocol (see Section 6.5), or the subject may be withdrawn at the discretion of the 
investigator (see Section 9.4).

Acute disease and/or fever at the time of vaccination.

Acute disease is defined as the presence of a moderate or severe illness with or 
without fever.

Fever is defined as temperature ≥ 37.5°C/99.5°F on oral, axillary or tympanic 
setting. The preferred route for recording temperature in this study will be 
axillary. (Amended: 29 January 2014)
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) 
without fever can be administered all vaccines.
7.6.
Concomitant medication/product and concomitant 
vaccination
At each study visit/contact, the investigator should question the subject about any 
medication/product taken and vaccination received by the subject.
7.6.1.
Recording of concomitant medications/products and 
concomitant vaccination
The following concomitant medications/products/vaccines must be recorded in the 
eCRF if administered during the indicated recording period:

All concomitant medications/products, except vitamins and dietary supplements, 
administered starting within 30 days following each dose of study vaccine.

Any concomitant vaccination administered in the period starting 30 days before the 
first dose of study vaccine and ending at the last study visit.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
71
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
72

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature 37.5°C/99.5°F for oral, axillary or tympanic route, or 
38.0°C/100.4°F for rectal route].

Any concomitant medications/products/vaccines listed in Section 7.6.2.

Any concomitant medication/product/vaccine relevant to a SAE* or administered at 
any time during the study period for the treatment of a SAE*.
*SAEs that are required to be reported per protocol.

Any medication administered for TB treatment throughout the entire study period.
7.6.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from ATP analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
ATP analysis. See Section 11.4 for study cohorts/data sets to be analysed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccines used during the study period.

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days) during the study period. For corticosteroids, this will mean 
prednisone 20 mg/day, or equivalent. Inhaled and topical steroids are allowed.

A vaccine not foreseen by the study protocol administered during the period starting 
from 30 days before each dose of vaccine and ending 30 days after.
In case an emergency mass vaccination for an unforeseen public health threat (e.g.: a 
pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its SPC or PI and 
according to the local governmental recommendations and provided a written 
approval of the Sponsor is obtained.

Immunoglobulins and/or any blood products administered during the study period.
7.7.
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses
At each study visit subsequent to the first vaccination visit, it must be verified if the 
subject has experienced or is experiencing any intercurrent medical condition. If it is the 
case, the condition(s) must be recorded in the eCRF.
Subjects may be eliminated from the ATP cohort for immunogenicity if, during the study, 
they incur tuberculosis disease or any other condition that has the capability of altering 
their immune response or are confirmed to have an alteration of their initial immune 
status.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
72
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
73
8.
HEALTH ECONOMICS
Not applicable.
9.
SAFETY
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol.
Each subject will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious.
9.1.
Safety definitions
9.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.
Examples of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after investigational vaccine(s)/product(s) 
administration even though they may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational vaccine(s)/product(s) or a concurrent medication (overdose per se 
should not be reported as an AE/SAE).

Signs, symptoms temporally associated with vaccine administration.

Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen).
AEs to be recorded as endpoints (solicited AEs) are described in Section 9.1.3. All other 
AEs will be recorded as UNSOLICITED AEs.
If subjects observe any large injection site reaction, they should contact the study 
personnel and visit the investigator’s office for evaluation as soon as possible.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
73
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
74
A large injection site reaction is:

a swelling that measures more than 100 mm across where the vaccine was given, 
or

a noticeable irregular/uneven swelling where the vaccine was given, or

a noticeable increase in size of the arm that interferes with or prevents everyday 
activities (e.g., writing, use of computer, school attendance, sleeping, etc.). 
In case of questions or uncertainties, the subject/subject’s parent(s)/guardian(s) should 
contact the investigator by phone and the investigator will determine whether or not a 
visit should be arranged.
The investigator will record detailed information describing the AE on a specific large 
injection site reaction screen in the eCRF. An SAE report should also be completed if 
the large injection site reaction meets the definition of SAE. (Amended: 29 January 
2014)
Examples of an AE DO NOT include:

Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF.
9.1.2.
Definition of a serious adverse event 
A serious adverse event is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation,
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
74
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
75
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE.
d.
Results in disability/incapacity, OR
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
e.
Is a congenital anomaly/birth defect in the offspring of a study subject.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation.
9.1.3.
Solicited adverse events
The following local (injection site) and general AEs will be solicited:
Table 20
Solicited adverse events (Amended: 29 January 2014)
Solicited local (injection site) AEs
Solicited general AEs
Pain at injection site
Fatigue
Redness at injection site*
Fever
Swelling at injection site
Respiratory Symptoms†
Headache
Malaise
Myalgia
*In case the principal investigator or designate is unable to determine the extent of redness on darkly pigmented skin, it 
will be reported as non-interpretable in the eCRF and Diary Card.
†Respiratory symptoms include cough, blood in sputum, purulent sputum, shortness of breath or difficulties 
breathing, chestwall pain
Note: Temperature will be recorded in the evening. Should additional temperature 
measurements be performed at other times of day, the highest temperature will be 
recorded in the eCRF.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
75
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
76
9.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments that are judged by the 
investigator to be clinically significant will be recorded as AE or SAE if they meet the 
definition of an AE or SAE (refer to Sections 9.1.1 and 9.1.2). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline 
and significantly worsen following the start of the study will also be reported as AEs or 
SAEs.
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
Toxicity grading scales for laboratory parameters [FDA, 2007] are presented in Table 21.
Table 21
Toxicity grading table for laboratory abnormalities (Amended: 29 
January 2014)
Mild
(Grade 1)
Moderate 
(Grade 2)
Severe (Grade 
3)
Potentially Life 
Threatening 
(Grade 4)*
Serum
Sodium – Hyponatremia mEq/L
132 – 134
130 – 131
125 – 129
< 125
Sodium – Hypernatremia mEq/L
144 – 145
146 – 147
148 – 150
> 150
Potassium – Hyperkalemia mEq/L
5.1 – 5.2
5.3 – 5.4
5.5 – 5.6
> 5.6
Potassium – Hypokalemia mEq/L
3.5 – 3.6
3.3 – 3.4
3.1 – 3.2
< 3.1
Glucose – Hypoglycemia mg/dL
65 – 69
55 – 64
45 – 54
< 45
Glucose – Hyperglycemia
Fasting – mg/dL
Random – mg/dL
100 – 110
110 – 125
111 – 125
126 – 200
>125
>200
Insulin requirements 
or hyperosmolar 
coma
Blood Urea Nitrogen BUN mg/dL
23 – 26
27 – 31
> 31
Requires dialysis
Creatinine – mg/dL
1.5 – 1.7
1.8 – 2.0
2.1 – 2.5
> 2.5 or requires 
dialysis
Calcium – hypocalcemia mg/dL
8.0 – 8.4
7.5 – 7.9
7.0 – 7.4
< 7.0
Calcium – hypercalcemia mg/dL
10.5 – 11.0
11.1 – 11.5
11.6 – 12.0
> 12.0
Magnesium – hypomagnesemia 
mg/dL
1.3 – 1.5
1.1 – 1.2
0.9 – 1.0
< 0.9
Phosphorous – hypophosphatemia 
mg/dL
2.3 – 2.5
2.0 – 2.2
1.6 – 1.9
< 1.6
CPK – mg/dL
1.25 – 1.5 x 
ULN***
1.6 – 3.0 x ULN
3.1 –10 x ULN
> 10 x ULN
Albumin – Hypoalbuminemia g/dL
2.8 – 3.1
2.5 – 2.7
< 2.5
--
Total Protein – Hypoproteinemia g/dL
5.5 – 6.0
5.0 – 5.4
< 5.0
--
Alkaline phosphate – increase by 
factor
1.1 – 2.0 x ULN 2.1 – 3.0 x ULN 3.1 – 10 x ULN
> 10 x ULN
Liver Function Tests –ALT, AST 
increase by factor
1.1 – 2.5 x ULN 2.6 – 5.0 x ULN
5.1 – 10 x ULN
> 10 x ULN
Bilirubin – when accompanied by any 
increase in Liver Function Test 
increase by factor
1.1 – 1.25 x 
ULN
1.26 – 1.5 x 
ULN
1.51 – 1.75 x 
ULN
> 1.75 x ULN
Bilirubin – when Liver Function Test 
1.1 – 1.5 x ULN 1.6 – 2.0 x ULN 2.0 – 3.0 x ULN
> 3.0 x ULN
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
76
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
77
Mild
(Grade 1)
Moderate 
(Grade 2)
Severe (Grade 
3)
Potentially Life 
Threatening 
(Grade 4)*
is normal; increase by factor
Cholesterol
201 – 210
211 – 225
> 226
---
Pancreatic enzymes - amylase, lipase
1.1 – 1.5 x ULN 1.6 – 2.0 x ULN 2.1 – 5.0 x ULN
> 5.0 x ULN
Haematology
Hemoglobin (Female) - g/dL
11.0 – 12.0
9.5 – 10.9
8.0 – 9.4
< 8.0
Hemoglobin (Female) change from 
baseline value - g/dL
Any decrease –
1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
Hemoglobin (Male) - g/dL
12.5 – 13.5
10.5 – 12.4
8.5 – 10.4
< 8.5
Hemoglobin (Male) change from 
baseline value – g/dL
Any decrease –
1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
WBC Increase - cell/mm
3
10,800 –
15,000
15,001 –
20,000
20,001 –
25,000
> 25,000
WBC Decrease - cell/mm
3
2,500 – 3,500
1,500 – 2,499
1,000 – 1,499
< 1,000
Lymphocytes Decrease - cell/mm
3
750 – 1,000
500 – 749
250 – 499
< 250
Neutrophils Decrease - cell/mm
3
1,500 – 2,000
1,000 – 1,499
500 – 999
< 500
Eosinophils - cell/mm
3
650 – 1500
1501 - 5000
> 5000
Hypereosinophilic
Platelets Decreased - cell/mm
3
125,000 –
140,000
100,000 –
124,000
25,000 –
99,000
< 25,000
PT – increase by factor (prothrombin 
time)
1.0 – 1.10 x 
ULN**
1.11 – 1.20 x 
ULN
1.21 – 1.25 x 
ULN
> 1.25 ULN
PTT – increase by factor (partial 
thromboplastin time)
1.0 – 1.2 x ULN
1.21 – 1.4 x 
ULN
1.41 – 1.5 x 
ULN
> 1.5 x ULN
Fibrinogen increase - mg/dL
400 – 500
501 – 600
> 600
--
Fibrinogen decrease - mg/dL
150 – 200
125 – 149
100 – 124
< 100 or associated 
with gross bleeding or 
disseminated 
intravascular 
coagulation (DIC)
Urine
Protein
Trace
1+
2+
Hospitalization or 
dialysis
Glucose
Trace
1+
2+
Hospitalization for 
hyperglycemia
Blood (microscopic) – red blood cells
per high power field (rbc/hpf)
1 - 10
11 – 50
> 50 and/or 
gross blood
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion
ULN is the upper limit of the normal range and is dependent on normal reference ranges per institutional parameters.
*The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example, a low sodium value that falls within a 
grade 3 parameter (125-129 mEq/L) should be recorded as a Grade 4 hyponatremia event if the subject had a new 
seizure associated with the low sodium value (source: FDA, 2007). (Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
77
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
78
9.1.5.
Adverse events of specific interest
9.1.5.1.
Potential immune-mediated diseases
Potential immune-mediated diseases (pIMDs) are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. AEs that need to be recorded and 
reported as pIMDs include those listed in Table 22.
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
78
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
79
Table 22
List of potential immune-mediated diseases
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve disorders, 
including paralyses/paresis 
(e.g. Bell’s palsy)

Optic neuritis

Multiple sclerosis

Transverse myelitis

Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other variants

Acute disseminated 
encephalomyelitis, including 
site specific variants: e.g. non-
infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculomyelitis

Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome

Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy 
and polyneuropathies 
associated with monoclonal 
gammopathy)

Narcolepsy

Systemic lupus erythematosus 

Scleroderma, including diffuse 
systemic form and CREST 
syndrome

Systemic sclerosis

Dermatomyositis

Polymyositis 

Antisynthetase syndrome

Rheumatoid arthritis, 

Juvenile chronic arthritis, 
(including Still’s disease)

Polymyalgia rheumatic

Spondyloarthritis, including 
ankylosing spondylitis, 
reactive arthritis (Reiter's 
Syndrome) and 
undifferentiated 
spondyloarthritis

Psoriatic arthropathy

Relapsing polychondritis

Mixed connective tissue 
disorder

Psoriasis

Vitiligo

Erythema nodosum

Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis)

Cutaneous lupus 
erythematosus

Alopecia areata

Lichen planus

Sweet’s syndrome

Morphoea
Liver disorders
Gastrointestinal disorders
Metabolic diseases

Autoimmune hepatitis

Primary biliary cirrhosis

Primary sclerosing cholangitis

Autoimmune cholangitis

Crohn’s disease

Ulcerative colitis

Ulcerative proctitis

Celiac disease

Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis)

Grave's or Basedow’s disease

Diabetes mellitus type I

Addison’s disease
Vasculitides
Others

Large vessels vasculitis including: giant cell 
arteritis such as Takayasu's arteritis and temporal 
arteritis.

Medium sized and/or small vessels vasculitis 
including: polyarteritis nodosa, Kawasaki's 
disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg–Strauss syndrome 
(allergic granulomatous angiitis), Buerger’s 
disease (thromboangiitis obliterans), necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody 
(ANCA) positive vasculitis (type unspecified), 
Henoch-Schonlein purpura, Behcet's syndrome, 
leukocytoclastic vasculitis.

Autoimmune hemolytic anemia

Autoimmune thrombocytopenia

Antiphospholipid syndrome

Pernicious anemia

Autoimmune glomerulonephritis (including IgA 
nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and 
mesangioproliferative glomerulonephritis)

Uveitis

Autoimmune myocarditis/cardiomyopathy

Sarcoidosis

Stevens-johnson syndrome

Sjögren’s syndrome

Idiopathic pulmonary fibrosis

Goodpasture syndrome

Raynaud’s phenomenon
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
79
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
80
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the 
final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely.
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start.
9.1.6.
Pregnancy
Female subjects who are pregnant or lactating at the time of vaccination must not receive 
additional doses of study vaccine/placebo but may continue other study procedures at the 
discretion of the investigator.
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE.
Note: The pregnancy itself should always be recorded on an electronic pregnancy report.
The following should always be considered as SAE and will be reported as described in 
Sections 9.3.1 and 9.3.3:

Spontaneous pregnancy loss, including:

spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation).

ectopic and molar pregnancy.

stillbirth (intrauterine death of foetus after 22 weeks of gestation).
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognized that national 
regulations might be different.

Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life).

Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion.
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the investigational vaccine(s)/product(s) 
will be reported to GSK Biologicals as described in Section 9.3.3. While the investigator 
is not obligated to actively seek this information from former study participants, he/she 
may learn of a pregnancy through spontaneous reporting.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
80
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
81
9.2.
Detecting and recording adverse events, serious adverse 
events and pregnancies
9.2.1.
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
All AEs starting within 30 days following administration of each dose of study 
vaccine/placebo must be recorded into the appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related.
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine/placebo and will end 180 days following administration of the last dose of study 
vaccine/placebo for each subject. See Section 9.3 for instructions on reporting of SAEs.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine/placebo.
SAEs that are related to the investigational vaccine/product will be collected and 
recorded from the time of the first receipt of study vaccine/placebo until the subject is 
discharged from the study.
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study.
The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccine/placebo and will end 180 days following administration of the last dose of 
study vaccine/placebo. See section 9.3 for instructions on reporting of pregnancies.
The time period for collecting and recording of pIMDs will begin at the first receipt of 
study vaccine/placebo and will end 180 following administration of the last dose of study 
vaccine/placebo. See section 9.3 for instructions on reporting of pIMDs.
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies 
is given in Table 23.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
81
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
82
Table 23
Reporting periods for adverse events, serious adverse events and pregnancies
Study activity
Pre-
vacc*
Dose 1
(V1)
7 d post
V1
30 d
post V1
Dose 2
(V2)
7 d post
V2
30 d
post V2
6 months post 
dose 2
Study Conclusion 
D 0
D 6
D 29
D 30
D 36
D 59
M 7
M36
Reporting of solicited 
AEs†
Reporting of unsolicited 
AEs
Reporting of SAEs
Reporting of SAEs 
related to the 
investigational product
Reporting of SAEs 
related to study 
participation or 
concurrent GSK 
medication/vaccine
Reporting of 
pregnancies
Reporting of pIMDs
* i.e. consent obtained. 
Pre-Vacc: pre-vaccination; V: vaccination; Post-V: post-vaccination; D: Day, M: Month
† For the safety and immune sub-cohort only
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
82
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
83
9.2.2.
Post-Study adverse events and serious adverse events
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 23. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the investigational vaccine/product, the investigator will 
promptly notify the Study Contact for Reporting SAEs.
9.2.3.
Evaluation of adverse events and serious adverse events
9.2.3.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of collecting AEs, the subject should be asked a non-leading 
question such as: “Have you felt different in any way since receiving the vaccine or since 
the previous visit?”
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to GSK Biologicals.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
83
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
84
9.2.3.2.
Assessment of adverse events
9.2.3.2.1.
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 24
Intensity scales for solicited symptoms in adults (Amended: 29 
January 2014)
Adults
Adverse Event
Intensity grade
Parameter
Pain at injection site
0
None
1
Mild: Any pain neither interfering with nor preventing 
normal every day activities.
2
Moderate: Painful when limb is moved and interferes with 
every day activities.
3
Severe: Significant pain at rest. Prevents normal every 
day activities.
Redness at injection site
Record greatest surface diameter in mm
Swelling at injection site
Record greatest surface diameter in mm
Fever*
Record temperature in °C/°F
Headache
0
Normal
1
Mild: Headache that is easily tolerated
2
Moderate: Headache that interferes with normal activity
3
Severe: Headache that prevents normal activity
Fatigue
0
Normal
1
Mild: Fatigue that is easily tolerated
2
Moderate: Fatigue that interferes with normal activity
3
Severe: Fatigue that prevents normal activity
Respiratory symptoms (cough, 
blood in sputum, purulent 
sputum, shortness of breath or 
difficulties breathing, chestwall 
pain)
0
No symptoms 
1
Mild: symptoms that are easily tolerated
2
Moderate: symptoms that interfere with normal activity
3
Severe: symptoms that prevent normal activity
Malaise
0
Normal
1
Malaise that is easily tolerated
2
Malaise that interferes with normal activity
3
Malaise that prevents normal activity
Myalgia
0
Normal
1
Myalgia that is easily tolerated
2
Myalgia that interferes with normal activity
3
Myalgia that prevents normal activity
*Fever is defined as temperature 37.5°C / 99.5°F for oral, axillary or tympanic route, or 38.0°C / 100.4°F for rectal 
route. The preferred route for recording temperature in this study will be axillary.
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
84
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
85
The intensity should be assigned to one of the following categories:
1 (mild)
=
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An AE which is sufficiently discomforting to interfere with normal 
everyday activities.
3 (severe)
=
An AE which prevents normal, everyday activities 
In adults, such an AE would, for example, prevent attendance at 
work and would necessitate the administration of corrective therapy.
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 9.1.2.
9.2.3.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between investigational vaccine/
product and the occurrence of each AE/SAE. The investigator will use clinical judgement 
to determine the relationship. Alternative plausible causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the investigational vaccine/product will be considered and 
investigated. The investigator will also consult the IB to determine his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the SAE report to GSK Biologicals. The investigator may change 
his/her opinion of causality in light of follow-up information and update the SAE 
information accordingly. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements.
In case of concomitant administration of multiple vaccines, it may not be possible to 
determine the causal relationship of general AEs to the individual vaccines administered. 
The investigator should, therefore, assess whether the AE could be causally related to 
vaccination rather than to the individual vaccines.
All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
“Is there a reasonable possibility that the AE may have been caused by the 
investigational vaccine/product?”
YES: There is a reasonable possibility that the vaccine(s) contributed to the AE.
NO:
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine(s). There are other, more likely causes and 
administration of the study vaccine(s) is not suspected to have contributed to the 
AE.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
85
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
86
If an event meets the criteria to be determined as ‘serious’ (see Section 9.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE.
Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the vaccines, if applicable.

Erroneous administration.

Other cause (specify).
9.2.3.3.
Assessment of outcomes
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as:

Recovered/resolved.

Recovering/resolving.

Not recovered/not resolved.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
9.2.3.4.
Medically attended visits
For each solicited and unsolicited symptom the subject experiences, the subject will be 
asked if he/she received medical attention defined as hospitalisation, or an otherwise 
unscheduled visit to or from medical personnel for any reason, including emergency 
room visits. This information will be recorded in the eCRF.
9.3.
Reporting of serious adverse events, pregnancies, and 
other events
9.3.1.
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals
SAEs that occur in the time period defined in Section 9.2.1 will be reported promptly to 
GSK within the timeframes described in Table 25, once the investigator determines that 
the event meets the protocol definition of a SAE.
Pregnancies that occur in the time period defined in Section 9.2.1 will be reported 
promptly to GSK within the timeframes described in Table 25, once the investigator 
becomes aware of the pregnancy.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
86
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
87
pIMDs that occur in the time period defined in Section 9.2.1 will be reported promptly to 
GSK within the timeframes described in Table 25, once the investigator becomes aware 
of the pIMD.
Table 25
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals
Type of Event
Initial Reports
Follow-up of Relevant Information on a Previous 
Report
Timeframe
Documents
Timeframe
Documents
SAEs
24 hours*
Electronic SAE report
24 hours*
Electronic SAE report
Pregnancies
2 weeks*
Electronic pregnancy 
report
2 weeks*
Electronic pregnancy report
pIMDs
24 hours**
Electronic SAE report
24 hours*
Electronic SAE report
* Timeframe allowed after receipt or awareness of the information.
**Timeframe allowed after the diagnosis is established and known to the investigator.
9.3.2.
Contact information for reporting serious adverse events and 
other events to GSK Biologicals
Study Contact for Reporting SAEs
Back-up Study Contact for Reporting SAEs
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: 
 or 
9.3.3.
Completion and transmission of SAE reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic SAE report 
WITHIN 24 HOURS. The SAE report will always be completed as thoroughly as 
possible with all available details of the event. Even if the investigator does not have all 
information regarding a SAE, the report should still be completed within 24 hours. Once 
additional relevant information is received, the report should be updated WITHIN 24 
HOURS. The investigator will always provide an assessment of causality at the time of 
the initial report.
9.3.3.1.
Back-up system in case the electronic SAE reporting system does not 
work
If the electronic SAE reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper SAE report and fax it to the GSK Biologicals 
Clinical Safety and Pharmacovigilance department within 24 hours. 
This back-up system should only be used if the electronic SAE reporting system is not 
working and NOT if the system is slow. As soon as the electronic SAE reporting system 
is working again, the investigator (or designate) must complete the electronic SAE report 
within 24 hours. The final valid information for regulatory reporting will be the 
information reported through the electronic SAE reporting system. 

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
87
29-JAN-2014
PPD
PPD

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
88
9.3.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS.
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report.
9.3.5.
Reporting of pIMDs to GSK Biologicals
Once onset of a new pIMD or exacerbation of a pre-existing pIMD is diagnosed (serious 
or non-serious) in a study subject, the investigator (or designate) must complete the 
information in the electronic SAE report WITHIN 24 HOURS after he/she becomes 
aware of the diagnosis. A field on the SAE report allows to specify that the event is a 
pIMD and whether it is serious or non serious. The SAE report will always be completed 
as thoroughly as possible with all available details of the event, in accordance with the 
pIMD standard questionnaire provided. Even if the investigator does not have all 
information regarding a pIMD, the report should still be completed within 24 hours. Once 
additional relevant information is received, the report should be updated WITHIN 24 
HOURS. The investigator will always provide an assessment of causality at the time of 
the initial report.
Refer to Section 9.3.3.1 for back-up system in case the electronic SAE reporting system 
does not work.
9.3.6.
Updating of SAE, pregnancy, and pIMD information after freezing 
of the subject’s eCRF
When additional SAE, pregnancy, or pIMD information is received after freezing of the 
subject’s eCRF, new or updated information should be recorded on a paper report, with 
all changes signed and dated by the investigator. The updated report should be faxed to 
the GSK Biologicals Clinical Safety and Pharmacovigilance department or to the Study 
Contact for Reporting SAEs (refer to the Sponsor Information Sheet) within the 
designated reporting time frames specified in Table 25.
9.3.7.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 9.3.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
88
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
89
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccine/product and unexpected. 
The purpose of the report is to fulfil specific regulatory and GCP requirements, regarding 
the product under investigation.
9.4.
Follow-up of adverse events, serious adverse events, and 
pregnancies
9.4.1.
Follow-up of adverse events and serious adverse events
9.4.1.1.
Follow-up during the study
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 25).
All SAEs and pIMDs (serious or non-serious) documented at a previous visit/contact and 
designated as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the end of the study.
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination.
9.4.1.2.
Follow-up after the subject is discharged from the study
The investigator will follow subjects:

with SAEs, pIMDs (serious or non-serious), or subjects withdrawn from the study as 
a result of an AE, until the event has resolved, subsided, stabilised, disappeared, or 
until the event is otherwise explained, or the subject is lost to follow-up.
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper SAE and/or 
pregnancy report as applicable.
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
89
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
90
9.4.2.
Follow-up of pregnancies
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the electronic pregnancy report and 
the SAE report if applicable. Generally, the follow-up period doesn’t need to be longer 
than six to eight weeks after the estimated date of delivery.
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE.
9.5.
Treatment of adverse events
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 7.6).
9.6.
Unblinding
GSK Biologicals’ policy (which incorporates ICH E2A guidance, EU Clinical Trial 
Directive and US Federal Regulations) is to unblind the report of any SAE which is 
unexpected and attributable/suspected to be attributable to the investigational 
vaccine/product, prior to regulatory reporting. The GSK Biologicals’ Central Safety 
Physician is responsible for unblinding the treatment assignment in accordance with the 
specified timeframes for expedited reporting of SAEs (refer to Section 9.3.1).
9.7.
Emergency unblinding
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency, or in the event of a serious medical condition, when knowledge of 
the study treatment is essential for the clinical management or welfare of the subject, as 
judged by the investigator.
The emergency unblinding process consists of the automated system SBIR that allows the 
investigator to have unrestricted, immediate and direct access to the subject’s individual 
study treatment.
The investigator has the option of contacting a GSK Biologicals’ On-call Central Safety 
Physician (or Backup) if he/she needs medical advice or needs the support of GSK to 
perform the unblinding (i.e. he/she cannot access the automated Internet-based system).
Any emergency unblinding must be fully documented by using the Emergency 
Unblinding Documentation Form, which must be appropriately completed by the 
investigator and sent within 24 hours to GSK Biologicals.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
90
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
91
GSK Biologicals’ Contact information for Emergency Unblinding
24/24 hour and 7/7 day availability
GSK Biologicals’ Central Safety Physician:
 (GSK Biologicals Central Safety Physician on-call)
GSK Biologicals’ Central Safety Physician Back-up:
Emergency Unblinding Documentation Form transmission:
Fax: 
 or 
9.8.
Subject card
Study subjects must be provided with the address and telephone number of the main
contact for information about the clinical study.
The investigator (or designate) must therefore provide a “subject card” to each subject. In 
an emergency situation this card serves to inform the responsible attending physician that 
the subject is in a clinical study and that relevant information may be obtained by 
contacting the investigator.
Subjects must be instructed to keep subject cards in their possession at all times.

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
91
29-JAN-2014
PPD
PPD
PPD
PPD

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
92
10.
SUBJECT COMPLETION AND WITHDRAWAL
10.1.
Subject completion
A subject who returns for the concluding visit/is available for the concluding contact 
foreseen in the protocol is considered to have completed the study.
10.2.
Subject withdrawal
Withdrawals will not be replaced.
10.2.1.
Subject withdrawal from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit/was not available for the concluding contact 
foreseen in the protocol.
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
Investigators will make an attempt to contact those subjects who do not return for 
scheduled visits or follow-up by means of phone calls and/or home visits by field 
workers.
Information relative to the withdrawal will be documented in the eCRF.The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself, or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Protocol violation (specify).

Consent withdrawal, not due to an adverse event*.

Moved from the study area.

Lost to follow-up.

Other (specify).
*In case a subject is withdrawn from the study because he/she has withdrawn consent, the 
investigator will document the reason for withdrawal of consent, if specified by the 
subject, in eCRF.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
92
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
93
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 9.4.1.2).
10.2.2.
Subject withdrawal from investigational vaccine
A ‘withdrawal’ from the investigational vaccine refers to any subject who does not 
receive the complete treatment, i.e. when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the investigational vaccine may not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study protocol.
Information relative to premature discontinuation of the investigational vaccine will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination/treatment was made by 
the subject himself/herself, or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal:

Serious adverse event.

Non-serious adverse event.

Other (specify).
10.3.
Extension study
At the end of the study (study conclusion visit/contact), the investigator will ask each 
subject if they are interested to participate in a long-term study. If a subject is not 
interested in participating in the long-term study the reason for refusal will be 
documented in the subject’s eCRF.
10.4.
Screen and baseline failures
Upon completion of all screening procedures (Refer to Table 7), the investigator, or 
designee, will review the inclusion/exclusion criteria for each subject. Subjects meeting 
all eligibility criteria will be scheduled to come for their baseline (Day 0) visit. Their 
screening information will be recorded on the appropriate screen of eCRF.
If the investigator believes there is a reasonable reason to do so, screening procedures 
(including, but not limited to, the QTF screening in the case of an intermediate result) 
may only be repeated once, either individually or in their entirety. (Amended: 29 
January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
93
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
94
11.
STATISTICAL METHODS
11.1.
Primary endpoint

Incident cases of Definite Pulmonary TB disease not associated with HIV-
infection, meeting the first case definition.
Over a period starting 1 month post-dose 2 and lasting up to 35 months post last 
vaccination.
Refer to section 4 for case definitions
11.2.
Secondary endpoints
Efficacy

Incident cases of Definite Xpert MTB/Rif positive Pulmonary TB disease not 
associated with HIV-infection, meeting the second case definition.
Over a period starting 1 month post-dose 2 and lasting up to 35 months post last 
vaccination.

Incident cases of Definite Pulmonary TB disease meeting the third case definition.
Over a period starting 1 month post-dose 2 and lasting up to 35 months post last 
vaccination.

Incident cases of Microbiological Pulmonary TB disease meeting the fourth case 
definition.
Over a period starting 1 month post-dose 2 and lasting up to 35 months post last 
vaccination

Incident cases of Clinical TB disease meeting the fifth case definition.
Over a period starting 1 month post-dose 2 and lasting up to 35 months post last 
vaccination
Refer to section 4 for case definitions.
Safety

Occurrence of SAEs.
During the entire study period

Occurrence of unsolicited AEs.
During the 30 day follow-up period following vaccination (day of vaccination and 29 
subsequent days after each vaccine dose)

Occurrence of solicited local and general AEs in the safety and immune sub-cohort.
During the 7 day follow-up period following vaccination (day of vaccination and 6 
subsequent days after each vaccine dose).
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
94
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
95

Occurrence of all pIMDs.
Over a period starting at Day 0 until 6 months post-dose 2.

Occurrence of grade 2 haematological and biochemical, in the safety and immune 
sub-cohort, levels at:
Days 0, 7, 30 and 37
(Amended: 29 January 2014)
Immunogenicity

Evaluation of CMI responses with respect to components of the study vaccine, in the 
safety and immune sub-cohort:

Determined by the frequency of M72-specific CD4+/CD8+ T-cells per million 
cells identified after in vitro stimulation, as expressing any combination of 
immune markers among CD40L, IL-2, IFN-and TNF-.. (Amended: 29 
January 2014)
Timepoints: prior to dose 1 (Day 0) and post-dose 2 (Day 60, Years 1, 2 and 3)

Evaluation of humoral immune responses with respect to components of the study 
vaccine, in the safety and immune sub-cohort:

Determined by M72-specific antibody titres as measured by ELISA.

Determined by seropositivity rates as measured by ELISA.
Timepoints: prior to dose 1 (Day 0) and post-dose 2 (Day 60, Years 1, 2 and 3).
11.3.
Determination of sample size
The primary objective is to demonstrate that the lower limit of the 90% CI of vaccine 
efficacy (VE), obtained from the Cox proportional hazards regression model (VE=1-
estimated hazard ratio) associated to the M72/AS01E vaccine in preventing first episodes
of definite pulmonary TB disease meeting the first case definition is >0. (Amended: 29 
January 2014)
Using a logrank test with 80% power for a true VE of 70% (hazard ratio of 30%)and a 
two-sided 10% significance level, the number of cases required for a fixed sample design 
is 21cases, based on the assumption that the hazard rates are proportional. (Amended: 29 
January 2014)
To obtain these 21 cases in total at final efficacy analysis, assuming a mean yearly attack 
rate of 0.55% in the control group, 2 years of follow-up for each subject and a rate of loss 
to follow-up of 15% due to drop out over the 2 years period, 3506 subjects need to be 
enrolled based on the logrank test and parameters described above. A planned follow-up 
time of 3 years for each subject allows to mitigate any lower than expected incidence 
rate and alternative to achieve a higher precision of the VE estimate at the final 
analysis. (Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
95
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
96
11.4.
Study cohorts/data sets to be analysed
11.4.1.
Total vaccinated cohort
The Total Vaccinated Cohort (TVC) will include all vaccinated subjects for whom data 
are available.
The TVC for efficacy will include all vaccinated subjects and will include all TB cases 
occurring post-dose 1.
The TVC analysis will be performed per treatment actually administered at dose 1.
(Amended: 29 January 2014)
11.4.2.
According-to-protocol cohort for analysis of safety
The ATP cohort for analysis of safety will include all vaccinated and eligible subjects:

Who have received at least one dose of study vaccine according to their random 
assignment.

For whom study vaccines have been administered according to protocol 
(administration site and route).

With sufficient data to perform an analysis of safety (at least one dose administered 
with safety follow-up).

Who have not received a vaccine that may lead to elimination from an ATP analysis.

For whom the randomisation code has not been broken.

Without randomisation failure.
For the analysis of solicited adverse events and clinical laboratory observations, the ATP 
cohort for safety will include subjects from the safety and immune sub-cohort only.
11.4.3.
According-to-protocol cohort for analysis of immunogenicity
The ATP cohort for immunogenicity will include all subjects from the safety and immune 
sub-cohort that:

Received two vaccinations according to protocol procedures within specified 
intervals.

Who complied with blood sampling schedules.

Who had biochemistry and haematology values within normal range before any 
vaccination (exclude only if all values were out of range).

For whom post vaccination blood samples are available.

Who did not receive a vaccine/medication that may lead to elimination of an ATP 
analysis.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
96
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
97

Who did not present with a medical condition that may lead to elimination of an ATP 
analysis.

For whom the randomization code has not been broken.

Without randomisation failure. (Amended: 29 January 2014)
11.4.4.
According-to-protocol cohort for analysis of efficacy
The ATP cohort for efficacy will include all subjects included in the Total Vaccinated 
cohort who received all vaccinations according to protocol procedures within specified 
intervals that contribute time at risk in the follow-up period starting one month post dose 
2 (Day 60).
The ATP cohort for efficacy will include all subjects:

Who received 2 doses of M72/AS01E or placebo according to their random 
assignment.

Received both vaccinations according to protocol procedures within specified 
intervals.

Who entered the evaluation period for efficacy starting one month post dose 2, i.e. 
who have entered into the efficacy surveillance period.

Who did not present with TB disease, according to any case definition, during the 
vaccination period (day of first vaccination up to 1 month post dose 2).

For whom the randomization code has not been broken.

Who did not receive a vaccine/medication that may lead to elimination of an ATP 
analysis.

Who did not present with a medical condition that may lead to elimination of an ATP 
analysis.

Without randomisation failure. (Amended: 29 January 2014)
11.5.
Derived and transformed data

The cut-off value for M72-specific antibody titres is 2.8 EU/mL.

A seronegative subject is a subject whose antibody titre is below the cut-off value of 
the assay, while a seropositive subject is a subject whose antibody titre is greater 
than or equal to the cut-off value.

The Geometric Mean Titre (GMT) calculations are performed by taking the anti-log 
of the mean of the log10 titre transformations. For descriptive statistics purposes 
only, antibody titres below the cut-off value of the assay will be given an arbitrary 
value of half the cut-off value for the purpose of GMT calculation.

For a given subject and a given immunogenicity measurement, missing or non-
evaluable measurements will not be replaced.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
97
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
98

For the analysis of solicited symptoms, missing or non-evaluable measurements will 
not be replaced. Therefore the analysis of the solicited symptoms based on the total 
vaccinated cohort will include only subjects with documented safety data (i.e. 
symptom screen completed).

For the analysis of unsolicited AEs/SAEs/concomitant medication, all vaccinated 
subjects will be considered and subjects who did not report an event will be 
considered as subjects without an event.
11.6.
Analysis of demographics
Demographics and baseline characteristics will be described by group and for each of the 
cohorts described above.
Demographic characteristics (age at first study vaccination, gender, and ethnicity), will be 
summarised as a whole and by group using descriptive statistics:

Frequency tables will be generated for categorical variable such as centre.

Mean, median, standard deviation will be provided for continuous data such as age.
11.7.
Analysis of efficacy
The ATP cohort for efficacy will be used for the primary analysis of efficacy. If the 
percentage of enrolled subjects excluded from the ATP cohort for analysis of efficacy is 
more than 5%, a second analysis based on the TVC will be performed to complement the 
primary analysis.
Vaccine efficacy will be estimated from a Cox proportional hazard regression model 
(VE=1-hazard ratio) and 90% CIs and Wald p-value will be derived. The primary 
analysis will be unadjusted but secondary analyses will evaluate the effect of potential 
covariates. (Amended: 29 January 2014)
At final efficacy analysis, the success criterion for the primary objective is the following:
The lower limit of the 90% two-sided confidence interval (CI) for the VE (using a Cox 
regression model) against first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the first case definition, is above 0%
(Amended:29 January 2014)
Kaplan-Meier survival curves for the vaccine and control groups will be presented 
together with p-values from the logrank test.
If the primary objective is met, the confirmatory secondary objective will be evaluated 
with the following success criterion:
The lower limit of the 90% two-sided CI for the VE (using a Cox regression model) 
against first occurrence of Definite pulmonary TB disease not associated with HIV-
infection, meeting the second case definition, is above 0%. (Amended: 29 January 2014)
(Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
98
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
99
For all other secondary efficacy objectives, Kaplan-Meier survival curves will be plotted 
and compared by means of the logrank test. The magnitude of the vaccine efficacy will 
be estimated using Cox regression.
(Amended: 29 January 2014)
11.8.
Analysis of immunogenicity
The primary analysis will be based on the ATP cohort for analysis of immunogenicity, 
which includes subjects from the safety and immune sub-cohort only. If, in any vaccine 
group, the percentage of vaccinated subjects with immunogenicity results excluded from 
the ATP cohort for analysis of immunogenicity is 5% or more, a second analysis based 
on the Total vaccinated cohort, including subjects from the safety and immune sub-cohort 
only, will be performed to complement the ATP analysis.
11.8.1.
CMI and humoral immune responses
11.8.1.1.
Within groups assessment
The following parameters will be tabulated at each scheduled time point, for each study 
group:

Descriptive statistics of the frequency of M72-specific CD4+ T cells per million cells 
identified after in vitro stimulation, as expressing at least two immune markers 
among CD40L, IL-2, TNF-and IFN-γ, after background subtraction.

Descriptive statistics of the frequency of M72-specific CD8+ T cells per million cells 
identified after in vitro stimulation, as expressing at least two immune markers 
among CD40L, IL-2, TNF-and IFN-γ, after background subtraction.

Description statistics of the frequency of M72-specific CD4+ T cells per million 
cells identified after in vitro stimulation, as expressing any combination of immune 
markers among CD40L, IL-2, TNF-and IFN-γ, after background subtraction.

Description statistics of the frequency of M72-specific CD8+ T cells per million 
cells identified after in vitro stimulation, as expressing any combination of immune 
markers among CD40L, IL-2, TNF-and IFN-γ, after background subtraction.

For anti-M72 antibodies,

Seropositivity rate with exact 95% CI.

GMTs with exact 95% CI.
(Amended: 29 January 2014)
11.9.
Analysis of safety
The primary analysis will be based on the TVC for analysis of safety. If, in any vaccine 
group, the percentage of vaccinated subjects excluded from the ATP cohort for analysis 
of safety is 5% or more, a second analysis based on the ATP cohort for analysis of safety 
will be performed to complement the TVC analysis.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
99
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
100
Analyses of solicited (local and general) AEs and clinical laboratory observations will 
be performed for the safety and immune sub-cohort only. (Amended: 29 January 
2014)
The following analyses will be performed:

The percentage of subjects with at least one local AE (solicited and/or unsolicited), 
with at least one general AE (solicited and/or unsolicited) and with any AE during 
the solicited follow-up period will be tabulated with exact 95% CI after each vaccine 
dose and overall. The percentage of doses followed by at least one local AE 
(solicited and/or unsolicited), by at least one general AE (solicited and/or 
unsolicited) and by any AE will be tabulated, overall vaccination course, with exact 
95% CI.

The percentage of subjects reporting each individual solicited local and general AE 
during the solicited follow-up period will be tabulated with exact 95% CI. The 
percentage of doses, followed by each individual solicited local and general AE will 
be tabulated, overall vaccination course, with exact 95% CI.

Injection site swelling and redness will be analysed using a 3-grade evaluation 
system [0 mm to 20 mm(grade 0); 20 to 50 mm (grade 1); > 50 to 100 mm (grade 
2); > 100 mm (grade 3)]. (Amended: 29 January 2014)

Occurrence of fever will be reported per 0.5°C cumulative increments. Duration and 
prevalence of fever will be presented. Fever will also be analysed using a 3-grade 
evaluation system [< 37.5C (grade 0); 37.5C but 38.0C (grade 1); > 38.0C 
but ≤ 39.5C (grade 2); > 39.5C (grade 3)].

The same tabulation will be performed for grade 3 AEs and for AEs with 
relationship to vaccination.

The percentage of subjects with at least one report of unsolicited AE classified by the 
Medical Dictionary for Regulatory Activities (MedDRA) and reported up to 30 days 
after vaccination will be tabulated with exact 95% CI. The same tabulation will be 
performed for grade 3 unsolicited AEs and for unsolicited AEs with a relationship to 
vaccination.

The percentage of subjects reporting AEs resulting in a medically attended visit will 
also be tabulated.

The number of subjects with grade 2 laboratory abnormalities will be tabulated.
SAEs, pIMDs, and withdrawal from the study due to an AE will be described.
11.10.
Interpretation of analyses
For the analysis of the primary objective, a predefined success criterion and an 
appropriate type I error control are defined (see Section 11.7). The confirmatory
secondary objective will be analysed only if the primary objective is met. Because of this 
hierarchy, the type I error is controlled. All other analyses will be descriptive with the 
aim to characterise the difference in TB incidence, reactogenicity and immunogenicity
between groups. These descriptive analyses should not be interpreted.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
100
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
101
11.11.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
11.11.1.
Sequence of analyses
All analyses (including interim analysis) will be conducted on data as clean as possible.
(Amended: 29 January 2014)

Primary analysis of efficacy will be performed when 21 cases of definite pulmonary 
TB disease, meeting the first case definition, have accumulated in the ATP cohort for 
efficacy, during the efficacy surveillance period starting 1 month post dose 2 (Day 
60) or at the latest when all subjects have completed the Month 24 visit. (Amended:
29 January 2014)

A final analysis of the primary epoch including all efficacy, safety and immunology 
data will be performed at the end of the study, i.e. when all subjects have completed 
their Month 36 visit.

A pooled analysis of efficacy data generated in this study and efficacy data generated 
in future efficacy studies is foreseen.
(Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
101
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
102
12.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
12.1.
eCRF instructions (Amended: 29 January 2014)
Inform™, a validated computer application, will be used as the method for data 
collection. 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
While completed eCRFs are reviewed by a Site Monitor designated by “The 
Collaboration” at the study site, omissions or inconsistencies detected by subsequent 
eCRF review may necessitate clarification or correction of omissions or inconsistencies 
with documentation and approval by the investigator or appropriately qualified designee. 
In all cases, the investigator remains accountable for the study data. 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties.
12.2.
Study Monitoring by “The Collaboration”
GSK and its partners in“The Collaboration” will monitor the study to verify that, 
amongst others, the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. (Amended: 29 
January 2014)
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose.
(Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
102
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
103
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the eCRF will serve as the source must be identified, agreed and 
documented in the source documentation agreement form. (Amended: 29 January 2014)
For eCRF, the monitor will mark completed and approved screens at each visit.
(Amended: 29 January 2014)
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and “The Collaboration” procedures.
12.3.
Record retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
“The Collaboration” will inform the investigator/institution of the time period for 
retaining these records to comply with all applicable regulatory requirements. However, 
the investigator/institution should seek the written approval of the sponsor before 
proceeding with the disposal of these records. The minimum retention time will meet the 
strictest standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures; otherwise, 
the minimum retention period will default to 15 years. 
The investigator/institution must notify “The Collaboration” of any changes in the 
archival arrangements, including, but not limited to archival at an off-site facility, transfer 
of ownership of the records in the event the investigator leaves the site. 
12.4.
Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK or 
“The Collaboration” may conduct a quality assurance audit. Regulatory agencies may 
also conduct a regulatory inspection of this study. Such audits/inspections can occur at 
any time during or after completion of the study. If an audit or inspection occurs, the 
investigator and institution agree to allow the auditor/inspector direct access to all 
relevant documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
103
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
104
12.5.
Posting of information on publicly available clinical trial 
registers and publication policy
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
Summaries of the results of GSK interventional studies (phase I-IV) are posted on 
publicly available results registers within 12 months of the primary completion date for 
studies of authorised vaccines and 18 months for studies of non-authorised vaccines. 
GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit.
12.6.
Provision of study results to investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
13.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
104
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
105
14.
REFERENCES
Centers for Disease Control and Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf
Donald PR. Childhood tuberculosis: the hidden epidemic. Int J Tuberc Lung Dis. 2004: 8 
(5); 627629.
EMA Guideline on the exposure to medicinal products during pregnancy: need for post-
authorization data (Doc. Ref. EMEA/CHMP/313666/2005) ‘adopted at Community level 
in May 2006;
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2009/11/WC500011303.pdf
Food and Drug Administration [FDA], 2007. Guidance for Industry, Toxicity Grading 
Scale for Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials.
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
yInformation/Guidances/Vaccines/ucm091977.pdf, accessed March 2012.
Fine PEM. Variation in protection by BCG: implications of and for heterologous 
immunity. Lancet. 1995; 346: 13391345.
Sterne JAC, Rodrigues LC, Guedes IN. Does the efficacy of BCG decline with time since 
Vaccination? Int J Tuberc Lung Dis.1998; 2 (3): 200207.
World Health Organisation [WHO]. BCG vaccine WHO position paper. Weekly 
epidemiological record. 2004; 79: 2540.
World Health Organisation [WHO], 2006. International Standards for Tuberculosis Care: 
Diagnosis, Treatment, Public Health; 
http://www.who.int/tb/publications/2006/istc_report.pdf), accessed 02 April 2012.
World Health Organisation [WHO], 2007. Verbal Autopsy Standards, Ascertaining and 
Attributing cause of death. 
http://www.who.int/healthinfo/statistics/verbal_autopsy_standards2.pdf, accessed April 
2012.
World Health Organisation [WHO], 2009. Treatment of tuberculosis guidelines, fourth 
edition.
http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf, accessed April 
2012.
World Health Organisation [WHO], 2013. Global tuberculosis report 2013;
http://www.who.int/tb/publications/global_report/en/, accessed 02 December 2013.
(Amended: 29 January 2014)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
105
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
106
APPENDIX A
LABORATORY ASSAYS
Haematology/biochemistry
A complete blood count (CBC), renal and liver function tests will be measured at regular 
intervals throughout the study period. Laboratory reference values will be maintained by 
the Investigator in the study file and made available to GlaxoSmithKline Biologicals’ 
Global Study Manager prior to study start.
Serum preparation
Serum for antibody determination will be collected at indicated time points. Blood for 
analysis of antibody responses will be obtained from each volunteer and allowed to clot 
for 30 minutes to 1 hour at room temperature, and serum will be separated and frozen at -
70C (+/- 5C) or below until tested. All blood samples will be labelled with the study 
number and date obtained.
Whole blood (by capillary or venous route) should be collected observing appropriate 
aseptic conditions. It is recommended that Vacutainertubes WITH integrated serum 
separator (e.g. Becton-Dickinson VacutainerSST or CorvacSherwood Medical) be 
used so as to minimize the risk of haemolysis and to avoid blood cell contamination of 
the serum when transferring to standard serum tubes.
Serology (Antibody responses)
Immunogenicity (antibody levels) will be determined by evaluating antibody (IgG) 
responses to M72 as measured using standard ELISA. The enzyme-linked immunoassay 
(ELISA) utilises antibody and antigen interactions to test for either the presence of 
specific antibodies or antigens in an unknown sample. The antigens are chosen from the 
evaluated vaccine based on what is likely to be an immunogenic component. Briefly, 
partially purified M72 antigen is pre-coated onto a 96-well plate. Serum samples are 
added directly to the plate followed by a secondary anti-human antibody conjugated with 
an enzyme. The addition of substrate provides a means of detecting the serum antibody 
that is specific for the antigens in question. Positive control, calibrators are run on each 
plate in order to assess the relative titre of each test sample. Negative controls are also 
run on each plate to ensure specificity.
The cut-off of the anti-M72 ELISA is defined as 2.8 EU/mL. The laboratory designated 
by GSK uses standard and validated techniques and maintains a quality assurance log that 
outlines the performance of this particular assay over time.
Cell-mediated immune responses
Stimulation of whole blood 
After collection, whole blood samples will be stimulated at 37°C with pool(s) of 
overlapping peptides covering the M72 antigen sequence and with the stimulation 
controls for 2 hours in the presence of anti-CD28 and anti-CD49d antibodies. Then, 
cytokine secretion inhibitor (Brefeldin A) will be added for an additional overnight 
incubation. The day after, red blood cells will be lysed and white blood cells will be 
washed and fixed prior to cryopreservation and kept in storage for subsequent cytometry 
analysis. 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
106
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
107
Intracellular Cytokine Staining (ICS) 
Intracellular fluorescent staining for cytokines (ICS) provides information on the 
frequency of cells responding to one particular antigen; it allows to define the frequency 
of CD4+ and CD8+ T lymphocytes expressing molecules involved in immunity such as 
IFN-, IL-2, TNF-, and/or CD40L (conventional CD4+ and CD8+ T cell response 
markers). Thawed cells will be stained for surface markers (e.g. CD4+ or CD8+ for T 
cells) and then fixed. Fixed cells will then be made permeable and stained with labelled 
cytokine-specific antibody. Cells will then be washed, re-suspended in PBS and analysed 
by flow cytometry.
Xpert MTB/RIF for Mtb detection
The Xpert MTB/RIF assay and the GeneXpert instrument consists of a single-use multi-
chambered plastic cartridge preloaded with liquid buffers and lyophilized reagent beads 
necessary for sample processing, DNA extraction, and hemi-nested real-time PCR. 
Clinical sputum samples are treated with a NaOH and isopropanol-containing sample 
reagent (SR). The SR is added at a 2:1 ratio to the sputum sample or sputum pellet and 
incubated for 15 min at room temperature. The treated sample is transferred into the 
cartridge, the cartridge is loaded into the GeneXpert instrument, and an automatic process 
completes the remaining assay steps. The assay cartridge also contains lyophilized 
Bacillus globigii spores which serve as an internal sample processing and PCR control. 
The spores are automatically resuspended and processed during the sample processing 
step, and the resulting B. globigii DNA is amplified during the PCR step. The standard 
user interface indicates the presence or absence of M. tuberculosis, the presence or 
absence of RIF resistance, and a semi quantitative estimate of M. tuberculosis
concentration (high, medium, low, and very low). Assays that are negative for M. 
tuberculosis and also negative for the B. globigii internal control are reported as invalid. 
The PCR assay amplifies a 192-bp segment of the M. tuberculosis rpoB gene in a 
heminested real-time PCR. The internal control heminested B. globigii assay is 
multiplexed with the M. tuberculosis assay. M. tuberculosis is detected using five 
overlapping molecular beacon probes (probes A to E) that are complementary to the 
entire 81-bp RIF resistance-determining “core” region of the wild-type rpoB gene (5, 7, 
14). Mutations in the rpoB gene target inhibit hybridization of one or more of the rpoB-
specific molecular beacons, reducing or eliminating the signal from the corresponding 
probes. M. tuberculosis is identified when at least two of the five rpoB-specific molecular 
beacons give a positive signal with cycle threshold (CT) values that are ≤ 38 and that 
differ by no more than two cycles. B. globigii DNA is detected when the single B. 
globigii molecular beacon produces a CT of < 38 cycles (adapted from: Blakemore, R.; 
Story, E.; Helb, D.; Kop, J.; Banada, P.; Owens, M.R.; Chakravorty, S.; Jones, M.; 
Alland, D. Evaluation of the Analytical Performance of the Xpert MTB/RIF assay. J Clin 
Microbiol. 2010, 48(7), 2495-501].
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
107
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
108
QuantiFERON® TB Gold assay
For evaluation of Mtb complex infection, whether tuberculosis disease, latent TB 
infection or past TB infection, the QuantiFERON®-TB Gold In-Tube Assay (Cellestis) 
will be used. QuantiFERON®-TB Gold In-Tube is an in vitro diagnostic test using 
peptide cocktails simulating ESAT-6, CFP-10 and TB7.7 proteins to stimulate cells in 
heparinised whole blood. These proteins are absent from all BCG strains and from most 
non-tuberculosis mycobacteria with the exception of M. kansarii, M. szulgai and M. 
marinum. The assay will be performed according to the manufacturer’s instructions. 
Briefly, blood is collected directly into QuantiFERON®-TB Gold collection tubes 
including a Nil Control tube, TB antigen tube and Mitogen Control tube. The tubes 
should be incubated for 16-24 hours at 37°C prior to harvesting plasma. IFN-
concentrations in plasma are determined using the QuantiFERON®-TB Gold ELISA kit.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
108
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
109
APPENDIX B
CLINICAL LABORATORIES
Table 26
GSK Biologicals’ laboratories
Laboratory
Address
GSK Biologicals Global Vaccine Clinical 
Laboratory, Rixensart
Biospecimen Reception - B7/44
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium
GSK Biologicals Global Vaccine Clinical 
Laboratory, North America- Laval
Biospecimen Reception - Clinical Serology
525 Cartier blvd West - Laval - Quebec - Canada - H7V 3S8
GSK Biologicals Global Vaccine Clinical 
Laboratory, Wavre-Nord Noir Epine
Avenue Fleming, 20 - B-1300 Wavre - Belgium
Table 27
Outsourced laboratories (Amended: 29 January 2014)
Laboratory
Address
CEVAC - University of Gent
De Pintelaan, 185 Gent
Belgium
Central laboratories
BARC South Africa Pty Ltd
Napier Road POB 8475
2000 Johannesburg
Republic of South Africa
KEMRI/CDC Research Station, Kenya
Busia Road POB 1578-40100
Kisumu
Kenya
CIDRZ Zambia
Alick Nkhata Road
Kalingalinga Clinic Grounds
Lusaka
Zambia
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
109
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
110
APPENDIX C
AMENDMENTS AND ADMINISTRATIVE CHANGES 
TO THE PROTOCOL
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 1
eTrack study number 
and Abbreviated Title(s)
115616 (TUBERCULOSIS-018)
Amendment number:
Amendment 1
Amendment date:
20 July 2012
Co-ordinating author:
, Project Manager Scientific Writing XPE 
Pharma & Science for GSK Biologicals
Rationale/background for changes: 
The protocol was amended due to a change in the formulation of the placebo to 
be used in the study. 
Also the maximum percentage of females/males to be enrolled in the study was 
changed to allow for rapid enrolment while assuring a balanced study population 
in terms of gender distribution.
Additional changes for recording height and weight were made in the study procedures 
table.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Section 5.1 Number of subjects/centres
To ensure the gender of the study population is equally distributed between females and 
males, a cap has been put on the number of subjects per gender to be enrolled. A 
maximum of 60 55% of subjects from the same gender will be enrolled in the study and 
enrolment of females/males will be stopped at approximately 4200 3850subjects of any 
gender maximum.

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
110
29-JAN-2014
PPD

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
111
Section 6.5 Outline of study procedures
Table 5
List of study procedures
Visit 1 
Screening visit 
Visit 2 Visit 3 1
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8 
Contact 5, 
6, 7, 8, 9 
Visit 9 
Contact 10, 
11, 12, 13, 14 
Visit 10 
Time point (s)
D -30 
D 0  
D 7  
D 30 
D 37  
D 44 
M 2 
M 4, 6, 8, 
10
M 12 
M 14, 16, 
18, 20, 22 
M 24 
M 26, 28, 30, 
32, 34 
M 36 
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
All subjects 
Informed consent
●
Check inclusion/exclusion 
criteria 
●
●
Collect demographic data
●
Medical history 
●
●
Physical examination
●
History-directed physical 
examination  
O
O
O
O
O
O
Resting vital signs 
O
O
O
HIV testing3 (2.5 mL/test)
●
Record weight and height4
●
●
●
●
Documentation of history of 
BCG vaccination/presence 
of scar  
●
Pregnancy test (-HCG 
urine) 
●
●
●
Study group and treatment 
number allocation
O
Treatment number allocation 
for second dose
O
Vaccination 
●
●
Recording of administered 
treatment number
●
●
Check contraindications to 
subsequent vaccination
●
●
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
111
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
112
Visit 1 
Screening visit 
Visit 2 Visit 3 1
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8 
Contact 5, 
6, 7, 8, 9 
Visit 9 
Contact 10, 
11, 12, 13, 14 
Visit 10 
Time point (s)
D -30 
D 0  
D 7  
D 30 
D 37  
D 44 
M 2 
M 4, 6, 8, 
10
M 12 
M 14, 16, 
18, 20, 22 
M 24 
M 26, 28, 30, 
32, 34 
M 36 
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Recording concomitant 
medication/vaccination 
●
●
●
●
●
●
●
●
●
●
●
●
●
Recording intercurrent 
medical condition
●
●
●
●
●
●
●
●
●
●
●
●
Distribution of diary cards 
O
O
Return of diary cards  
O
O
Recording of unsolicited AEs 
● 
● 
● 
● 
● 
● 
Pre-vaccination assessment 
(including temperature) 
●
●
Blood sampling for RNA 
expression profiling (2.5 
mL)5
●
●
Reporting SAEs  
●6
●
●
●
●
●
●
●7
●6
●6
●6
●6
●6
Reporting pIMDs
●
●
●
●
●
●
●8
Reporting pregnancy 
●
●
●
●
●
●
●8
Diagnostic procedures for 
suspected pulmonary TB9
●
●
●
●
●
●
●
●
●
●
●
●
●
Documentation of TB 
cases10
●
●
●
●
●
●
●
●
●
●
●
Safety and immune sub-
cohort
Measuring Vitamin D 
●
Recording of solicited AEs  
●
●
●
●
CBC (Hb, PLT and WBC), 
ALT, AST, creatinine, 
bilirubin (8 mL)
●
●
●
●
Blood sampling for CMI (
18 mL)
●
●
●
●
●
●
●
●
Blood sampling for humoral 
immunogenicity (2 mL)
●
●
●
●
●
●
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
112
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
113
Visit 1 
Screening visit 
Visit 2 Visit 3 1
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8 
Contact 5, 
6, 7, 8, 9 
Visit 9 
Contact 10, 
11, 12, 13, 14 
Visit 10 
Time point (s)
D -30 
D 0  
D 7  
D 30 
D 37  
D 44 
M 2 
M 4, 6, 8, 
10
M 12 
M 14, 16, 
18, 20, 22 
M 24 
M 26, 28, 30, 
32, 34 
M 36 
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Blood sampling for 
QuantiFERON assay
(3 mL)
●
●
●
●
Study conclusions for all 
subjects
●
Note: The double border at Month 36 indicates the final analyses which will be performed on all data obtained up to month 36.
Pre V: Pre Vaccination; V: Vaccination; Post V: Post Vaccination
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
1 Only subjects in the safety and immune sub-cohort need to come for this visit.
2 The most informative time point for collection of blood samples for RNA expression profiling post dose 2 will be determined in a separate study (116777 [TUBERCULOSIS-019]). 
Depending on the results of this study, the exact time point for blood sampling post dose 2 (Visit 6) will be determined. The exact time point will be communicated to the investigators 
appropriately at the latest at study initiation.
3 HIV testing and pre-test counselling will be performed at screening in areas were HIV-prevalence > 1%.
4 Weight and height also needs to be recorded at the time of first occurrence of whenever TB disease is confirmed (definite and clinical).
5 Samples for RNA expression profiling will also be taken at the time of TB diagnosis.
6 Only SAEs related to study participation or concurrent GSK medication/vaccine.
7 SAEs not related to study participation or concurrent GSK medication/vaccines will be recorded until 6 months post dose 2 (M7).
8 To be recorded until 6 months post dose 2 (M7).
9 Sputum samples for Xpert MTB/RIF testing and microbiological culture will be taken throughout the study if a subject presents with clinical suspicion of pulmonary TB disease. At 
screening, only samples for Xpert MT/RIF will be collected when a subject presents with clinical suspicion of TB disease. Three sputum samples, preferably taken in the morning and 
within one week, must be collected. Additionally, when a subject is diagnosed with TB, an HIV test must be performed (2.5 mL/test). If the subject is confirmed HIV-positive, blood 
samples must be taken (2.5 mL) to measure CD4 counts.
10 Documentation of TB cases will be done throughout the study; this includes documentation of cases during active and passive follow-up and monitoring of medical facilities and 
pharmacies.
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
113
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
114
Section 7.1 Description of study vaccines
Table 17
Study vaccines 
Treatment 
name
Vaccine/product 
name
Formulation
Presentation
Volume to be 
administered
Number 
of doses
M72/AS01E
M72
M72 (10 µg); sucrose; 
polysorbate; TRIS
Lyophilised 
cake in vial
0.5 ml
2
AS01E
25µg MPL, 25 µg QS21 in a 
liposome-based formulation
Liquid in vial
Placebo
Placebo pellet
5 % Sucrose in phosphate 
buffer
Lyophilised 
cake in vial 
0.5 ml 
2
Placebo adjuvant
23.8 14.8µg α-Tocopherol, 
21.4 µg squalene and 
9.7 µg Tween 80
Liquid in vial 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
114
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
115
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 2
eTrack study number 
and Abbreviated Title:
115616 (TUBERCULOSIS-018)
Amendment number:
Amendment 2
Amendment date:
10 September 2012
Co-ordinating author:
, Scientific Writer XPE 
Pharma&Science, contractor for GSK Biologicals
Rationale/background for changes:
!
Less informative time points (Days 7, 30 and 37) for blood sampling for cell-
mediated immune responses and humoral immune responses (Day 30) were 
removed to reduce the logistical burden on the study centres.
!
HIV diagnostic testing at screening and at the time of TB diagnosis, was adapted 
to align with local clinical practice.
!
Due to the limitations of the statistical program, the confidence intervals and the 
two-sided alpha values were adjusted for the interim and final analyses.
!
The definition of clinical suspicion of pulmonary TB was updated.
!
To ascertain sufficient volume for diagnostic testing, the sputum sample volume 
was increased.
!
Diary card completion guidelines were added.
!
Diagnostic testing at screening for subjects with signs and symptoms of TB disease 
was removed. Subjects with clinical suspicion of TB disease at the time of 
screening will not be included in the study.
!
To illustrate the collaboration between GSK Biologicals and Aeras in the 
operational conduct of the study the term ‘The collaboration’ was introduced and 
inserted where applicable.
!
Additional minor corrections were made.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Title page
Contributing Authors Aeras
!
, Chief Scientific Officer
!
, Director Clinical Development

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
115
29-JAN-2014
PPD
PPD
PPD

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
116
Synopsis
Objectives
Primary
Success criterion:
The lower limit of the 95.0295.1% two-sided confidence interval (CI) for the VE against 
first occurrence of Definite pulmonary TB disease not associated with HIV-infection, 
meeting the first case definition, is above 0%.
Secondary
Efficacy
Success criterion:
The lower limit of the 95.02 95.1% two-sided confidence interval (CI) for the VE against 
first occurrence of Definite Xpert MTB/Rif positive pulmonary TB disease not associated 
with HIV-infection, meeting the second case definition, is above 0%
Study design

Sampling schedule:

Blood samples will be collected in the safety and immune sub-cohort for 
evaluation of biochemistry/haematology parameters (Days 0, 7, 30 and 37), CMI 
responses (Days 0, 7, 30, 37, 60 and Years 1, 2 and 3), humoral immune 
responses (Days 0, 30, 60 and Years 1, 2 and 3) and QuantiFERON status (Day 0 
and Years 1, 2 and 3).

Blood samples for RNA expression profiling will be collected from all subjects
(Days 0, and post dose 2 and when TB is diagnosed).
Case definitions
Fourth Case definition – Definite pulmonary TB
*Clinical suspicion of pulmonary TB is defined as a subject presenting with one or more 
of the following symptoms: unexplained cough > 1-2 weeks, unexplained fever > 1 
week, night sweats, unintentional weight loss, pleuritic chest pains, haemoptysis, fatigue 
or shortness of breath on exertion.
Endpoints
Secondary
Immunogenicity

Evaluation of CMI responses with respect to components of the study vaccine, in the 
safety and immune sub-cohort:
Time points: prior to dose 1 (Day 0), post dose 1 (Days 7 and 30) and post dose 2 
(Days 37, 60 and Years 1, 2 and 3).
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
116
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
117

Evaluation of humoral immune responses with respect to components of the study 
vaccine, in the safety and immune sub-cohort:
Time points: prior to dose1 (Day0), post dose 1 (Day 30) and post dose 2 (Day 60 
and Years 1, 2 and 3)
Tertiary

Description of RNA expression profile signatures in selected samples as a correlate 
of risk to describe protective and non-protective immune responses after 2 doses of 
M72/AS01E.
Time points: Prior to dose 1 (Day 0) and post dose 2 and when TB is diagnosed.
Glossary of terms
Clinical suspicion of 
pulmonary TB
A subject has clinical suspicion of pulmonary TB when he/she 
presents with one or more of the following symptoms: 
unexplained cough > 1-2 weeks, unexplained fever > 1 week, 
night sweats, unintentional weight loss, pleuritic chest pains, 
haemoptysis, fatigue or shortness of breath on exertion.
“The Collaboration”
Refers to the joint collaboration between GSK Biologicals 
and Aeras. GSK will act as the sponsor of this study whereas 
Aeras will provide financial and operational support.
1.2. Collaboration between GSK Biologicals and Aeras
This study is a joint collaboration between GSK Biologicals and Aeras, referred to as 
“The Collaboration” in the remainder of this document.
2.1. Primary objective
Success criterion to be used for the primary objective:
The lower limit of the 95.0295.1% two-sided confidence interval (CI) for the VE against 
first occurrence of Definite pulmonary TB disease not associated with HIV-infection, 
meeting the first case definition, is above 0%.
2.2. Secondary objectives
Efficacy
If the primary objective is met, this secondary objective will be analysed using the 
following success criterion:
The lower limit of the 95.0295.1% two-sided confidence interval (CI) for the VE against 
first occurrence of Definite Xpert MTB/Rif positive pulmonary TB disease not associated 
with HIV-infection, meeting the second case definition, is above 0%.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
117
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
118
3. Study Design Overview
Sampling schedule:

Blood samples will be collected in the safety and immune sub-cohort for evaluation 
of biochemistry/haematology parameters (Days 0, 7, 30 and 37), CMI responses
(Days 0, 7, 30, 37 and 60 and Years 1, 2 and 3), humoral immune responses (Days 0, 
30 and 60 and Years 1, 2 and 3) and QuantiFERON status (Days 0 and Years 1, 2 
and 3).

Blood samples for RNA expression profiling will be collected from all subjects at 
predefined time points (Days 0 and Day 44*) and whenever a subject is diagnosed 
with TB disease.
* The most informative time point for collection of blood samples for RNA 
expression profiling post-dose 2 will be determined. The exact time point will be 
communicated to the investigators appropriately at the latest at study initiation.
Diagnostic procedures for suspected Pulmonary TB: At screening, when a subject 
presents with clinical suspicion of pulmonary TB, three respiratory sputum samples, 
preferably taken in the morning, within a one week interval, must be collected for testing 
with Xpert MTB/RIF to rule out pulmonary TB disease. during the entire study, when a 
subject presents with clinical suspicion of pulmonary TB, three respiratory sputum 
samples, preferably taken in the morning, within a one week interval, must be collected 
for testing with Xpert MTB/RIF and microbiological culture.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
118
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
119
5.1. Number of subjects/centres
There will be one sub-cohort for safety/reactogenicity and immunogenicity. A maximum 
of 500 eligible subjects from selected centres in India and South Africa and Kenya will 
be included in this safety and immune sub-cohort (Table 4).
Table 4
Sub-cohorts
Sub-cohort 
name
Description
Estimated number 
of subjects
Safety and 
immune sub-
cohort
Safety parameters for this sub-cohort will be collected as follows:

Solicited AEs will be collected for 7 days (day of vaccination and 
6 subsequent days) following vaccination.

Serum biochemistry/haematology values will be measured at 
Days 0, 7, 30, and 37.
Approximately 450
Immunogenicity:

Humoral immunogenicity will be evaluated by measuring M72-
specific IgGs at Days 0, 30 and 60 and Years 1, 2 and 3.

CMI will be evaluated by measuring M72-specific CD4+ and 
CD8+ T cells expressing at least 2 immune markers (CD40-L 
and/or IFN-γ and/or IL-2 and/or TNF-) at Days 0, 7,30, 37 and 
60 and Years 1, 2 and 3.

The QuantiFERON status of subjects will be determined at Day 
0 and Years 1, 2 and 3.
5.2. Inclusion criteria for enrolment

Healthy subjects or those with chronic well-controlled disease as established by 
medical history and clinical examination before entering into the study.
6.2.2.1. Randomisation of supplies
To allow GSK Biologicals “The Collaboration” to take advantage of greater rates of 
recruitment than anticipated at individual centres in this multi-centre study and to thus 
reduce the overall study recruitment period, an over-randomisation of supplies will be 
prepared.
6.2.2.2.1. Study group and treatment number allocation
Allocation of the subject to a study group at the investigator site will be performed using 
a randomisation system on internet (SBIR). The randomisation algorithm will use a 
minimisation procedure accounting for:

Gender: a maximum of 3850 4200 females/males will be recruited. 

TB disease categorised as history or no history of TB disease.
Minimisation factors will have equal weight in the minimisation algorithm.
6.2.3 Allocation of subjects to assay subsets
Approximately 500 subjects will be included in the safety and immune sub-cohort. These 
subjects will be enrolled at selected centres in India, and South Africa and Kenya. 
Subjects included in the sub-cohort will be equally distributed between Africa and India. 
Blood sampling and safety assessment will be performed as described in Table 4.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
119
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
120
6.4.1 Surveillance for safety and efficacy
Surveillance for efficacy starts with administration of the first dose of study vaccine or 
placebo.
6.4.1.1. Active follow-up for safety and efficacy
Subject safety follow-up and timely case capture of incident TB disease is of paramount 
importance. In addition to study visits at the study facilities, regular contacts (every two 
months) with the study subjects must be maintained using one or more of the following 
methods:

Regular interval home visits by site staff field workers

Phone calls to inquire about current health status, completed by home visits if the 
subject cannot be reached.

2-way short message service (SMS) exchange.
These active follow-up procedures for surveillance of safety and efficacy will be 
described in local study Standard Operating Procedures and Informed Consent Forms. 
Informed Consent Forms will be submitted to the Ethics Committee for approval prior to 
implementation.
6.4.1.2. Passive follow-up for efficacy
6.4.2. Diagnostic procedures for the detection of suspected pulmonary TB
At screening, when a subject presents with clinical suspicion of pulmonary TB, three 
respiratory sputum samples, preferably taken in the morning, must be collected, within a 
one week interval, for testing with Xpert MTB/RIF to rule out pulmonary TB disease.
[…]
The method of diagnosis and results must be recorded in the subjects’ eCRF.
Height and wWeight of the subject must also be recorded in the subjects’ eCRF at the 
time of TB diagnosis.
[…]
In case smear microscopy is performed to diagnose pulmonary TB, the results must be 
recorded in the subjects’ eCRF.
Height and weight of the subject must also be recorded in the subjects’ eCRF at the time 
of TB diagnosis.
6.4.5.2. Independent Data Monitoring Committee
An independent statistical team (i.e., comprising members who are not neither GSK 
employees neither Aeras employees and who are not involved in the study management) 
will be appointed by GSK Biologicals. This team will be unblinded to treatment 
assignment and provide all necessary tables, listings, figures and individual subject data 
to the IDMC.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
120
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
121
6.5. Outline of study procedures
Table 5
List of study procedures
Visit 1 
Screening visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8
Contact 5, 
6, 7, 8, 9
Visit 9
Contact 10, 
11, 12, 13, 14
Visit 10
Time point(s)
D-30
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
All subjects 
Informed consent
●
Check inclusion/exclusion 
criteria
●
●
Collect demographic data
●
Medical history
●
●
Physical examination
●
History-directed physical 
examination
O
O
O
O
O
O
Resting vital signs
O
O
O
HIV testing3 (up to 2.5 
mL/test)
●
Record weight4
●
●
●
●
Documentation of history of 
BCG vaccination/presence of 
scar
●
Pregnancy test (-HCG urine)
●
●
●
Study group and treatment 
number allocation
O
Treatment number allocation 
for second dose
O
Vaccination 
●
●
Recording of administered 
treatment number
●
●
Check contraindications to 
subsequent vaccination
●
●
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
121
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
122
Visit 1 
Screening visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8
Contact 5, 
6, 7, 8, 9
Visit 9
Contact 10, 
11, 12, 13, 14
Visit 10
Time point(s)
D-30
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Recording concomitant 
medication/vaccination
●
●
●
●
●
●
●
●
●
●
●
●
●
Recording intercurrent medical 
condition
●
●
●
●
●
●
●
●
●
●
●
●
Distribution of diary cards
O
O
Return of diary cards
O
O
Recording of unsolicited AEs 
●
●
●
●
●
●
Pre-vaccination assessment 
(including temperature)
●
●
Blood sampling for RNA 
expression profiling (2.5 
mL)5
●
●
Reporting SAEs
●6
●
●
●
●
●
●
●7
●6
●6
●6
●6
●6
Reporting pIMDs
●
●
●
●
●
●
●8
Reporting pregnancy
●
●
●
●
●
●
●8
Diagnostic procedures for 
suspected pulmonary TB9
●
●
●
●
●
●
●
●
●
●
●
●
●
Documentation of TB cases10
●
●
●
●
●
●
●
●
●
●
●
Safety and immune sub-
cohort
Measuring Vitamin D
●
Recording of solicited AEs
●
●
●
●
CBC (Hb, PLT and WBC), 
ALT, AST, creatinine, bilirubin 
(8 mL)
●
●
●
●
Blood sampling for CMI (18 
mL)
●
●
●
●
●
●
●
●
Blood sampling for humoral 
immunogenicity (2 mL)
●
●
●
●
●
●
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
122
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
123
Visit 1 
Screening visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8
Contact 5, 
6, 7, 8, 9
Visit 9
Contact 10, 
11, 12, 13, 14
Visit 10
Time point(s)
D-30
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Blood sampling for 
QuantiFERON assay
(3 mL)
●
●
●
●
Study conclusions for all 
subjects
●
Note: The double border at Month 36 indicates the final analyses which will be performed on all data obtained up to month 36. 
Pre V: Pre Vaccination; V: Vaccination; Post V: Post Vaccination
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
1 Only subjects in the safety and immune sub-cohort need to come for this visit.
2 The most informative time point for collection of blood samples for RNA expression profiling post dose 2 will be determined in a separate study (116777 [TUBERCULOSIS-019]). 
Depending on the results of this study, the exact time point for blood sampling post dose 2 (Visit 6) will be determined. The exact time point will be communicated to the investigators 
appropriately at the latest at study initiation.
3 HIV testing and pre-test counselling will be performed at screening in areas were HIV-prevalence > 1%, according to the procedures detailed in Table 8.
4 Weight also needs to be recorded whenever TB disease is confirmed (definite or clinical).
5 Samples for RNA expression profiling will also be taken at the time of TB diagnosis.
6 Only SAEs related to study participation or concurrent GSK medication/vaccine.
7 SAEs not related to study participation or concurrent GSK medication/vaccines will be recorded until 6 months post dose 2 (M7).
8 To be recorded until 6 months post dose 2 (M7).
9 Sputum samples for Xpert MTB/RIF testing and microbiological culture will be taken throughout the study if a subject presents with clinical suspicion of pulmonary TB disease. Three 
sputum samples, preferably taken in the morning and within one week, must be collected. Additionally, when a subject is diagnosed with TB, HIV testing must be performed 
according to the procedures detailed in Table 8. Up to 2.5mL of blood will be collected per test. If the subject is confirmed HIV-positive, blood samples must be taken (2.5 mL) 
to measure CD4 counts.
10 Documentation of TB cases will be done throughout the study, starting at Visit 3 (Day 7); this includes documentation of cases during active and passive follow-up and monitoring 
of medical facilities and pharmacies.
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
123
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
124
Table 6
Intervals between study visits
Interval
Allowed interval1
Visit 1 - Visit 2
30 days - 1 days
Visit 2 - Visit 4
26 days - 35 days
Visit 4 - Visit 6
1 days - 25 days 2
Visit 4 - Visit 7
14 days - 35 days
Visit 4 - Visit 8
10 months - 12 months
Visit 4 - Visit 9
22 months -24 months
Visit 4 - Visit 10
34 months - 36 months
Visit n – next contact
6 weeks – 12 weeks
Contact n – contact n+1
6 weeks – 12 weeks
1 Subjects may not be eligible for inclusion in the ATP cohort for analysis of immunogenicity and efficacy if they make 
the study visit outside this interval.
2 The most informative time point for collection of blood samples for RNA expression profiling post dose 2 will be 
determined in a separated study (116777 [TUBERCULOSIS-019]). Depending on the results of this study, the exact 
time point for blood sampling post dose 2 (Visit 6) will be determined. The exact time point will be communicated to the 
investigators appropriately at the latest at study initiation.
6.6.1. Informed consent
The signed/witnessed/thumb printed informed consent of the subject must be obtained 
before study participation. Refer to Section 6.1 for the requirements on how to obtain 
informed consent as appropriate. Consenting and screening may be repeated, but only 
once, for subjects who would return out of screening interval but still agree to 
participate.
6.6.11.1. Blood sampling for safety or immune response assessments

For all subjects included in the safety and immune sub-cohort:

A volume of at least 8 mL of whole blood should be drawn for tests performed 
to assay for CBC, ALT, AST, AP, bilirubin and creatinine at each predefined 
time point (Table 8). Vitamin D levels will be measured at Day 0 only.

For all subjects:

At screening, HIV testing must be performed according to the procedures 
detailed in Table 8 in regions with high HIV prevalence (>1 %). Up to 
approximately 2.5 mL of blood will be collected for each test.

When a subject is diagnosed with TB disease, HIV testing must be performed 
according to the procedures detailed in Table 8. Up to approximately 2.5 mL of 
blood will be collected for each test. at least 2.5 mL of blood will be collected 
for HIV testing. If the initial HIV test is positive, a confirmatory HIV test must 
be performed (at least 2.5 mL). Additionally, if HIV is confirmed, at least 2 mL 
of blood will be collected to measure CD4 counts.

*Blood sampling for RNA expression profiling is planned for Day 0 (Visit 2) and 
Visit 6 (post dose 2). The most informative time point for collecting whole blood 
samples for RNA expression profiling post dose 2 will be determined in a 
separate study (116777 [TUBERCULOSIS-019 ). Depending on the results of 
this study, the exact time point for blood sampling post dose 2 (Visit 6) will be 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
124
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
125
determined. The exact time point will be communicated to the Investigators 
appropriately at the latest at study initiation.
6.6.11.2. Sputum sample collection for TB diagnosis
All subjects will be required to provide 3 sputum samples, preferably taken in the 
morning, within a one week interval, of at least approximately 1.5 5 mL to test for Mtb 
using the Xpert MTB/RIF assay and microbiological culture whenever the subject 
presents with clinical suspicion of pulmonary TB. At screening, only Xpert MTB/RIF 
testing will be performed if the subject presents with clinical suspicion of pulmonary TB, 
to rule out definite pulmonary TB disease. If needed, induction of sputum through 
nebulisation of hypertonic saline may be performed.
6.6.15. Recording of AEs, SAEs, pregnancies and pIMDs

At each vaccination visit, diary cards will be provided to the subjects. Any 
unsolicited AEs (i.e. on the day of vaccination and during the next 29 days) 
occurring after vaccination will be recorded by all subjects. The subjects included in 
the safety and immune sub-cohort will also record body (axillary) temperature and 
any solicited local/general AEs (i.e. on the day of vaccination and during the next 6 
days). In case of illiterate subjects, a designated person (such as a family member 
or a field worker) may provide assistance to complete the diary cards. The subject 
will be instructed to return the completed diary card to the investigator at a later visit.
In case a diary card is lost by the subject or he/she is unable to complete the diary 
card, the safety information should be captured retrospectively using a descriptive 
interview. This process will be documented by an Internal Operational Procedure 
(IOP). Please refer to the SPM for further details.
6.7.1. Use of specified study materials
When materials are provided by GSK Biologicals “The Collaboration”, it is 
MANDATORY that all clinical samples (including serum samples) be collected and 
stored exclusively using those materials in the appropriate manner. The use of other 
materials could result in the exclusion of the subject from the ATP analysis (See Section 
11.5 for the definition of study cohorts/ data sets to be analysed). The investigator must 
ensure that his/her personnel and the laboratory(ies) under his/her supervision comply 
with this requirement. However, when GSK Biologicals “The Collaboration” does not 
provide material for collecting and storing clinical samples, appropriate materials from 
the investigator’s site must be used.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
125
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
126
6.7.2. Biological samples
Table 8
Biological samples
Sample type
Quantity
Unit
Time point
Subjects
Blood sampling for 
Safety assessment
At least 8
mL
Days 0, 7, 30 and 371
Safety and immune 
sub-cohort2
Blood sampling for 
Humoral responses
At least 2
mL
Days 0, 30, 60 and Years 1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for CMI
At least 18
mL
Days 0, 7, 30, 37, 60 and Years 
1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for for 
QuantiFERON® TB Gold 
At least 3
mL
Day 0 and Years 1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for RNA 
expression profiling
At least 2.5
mL
Days 0 and Day 443 and when 
TB diagnosed is confirmed
All subjects
Sputum sampling for TB 
diagnosis4
at least 1.5
Approximately 5
mL
Throughout the study when 
pulmonary TB is suspected
All subjects with 
suspicion of 
pulmonary TB
Blood sampling for initial 
HIV testing - Step 1 
(Rapid test)
Finger prick or 
Aat least 2.5
mL
At screening and whenever a 
subject is diagnosed with TB
All subjects5 living in 
a region with HIV 
prevalence > 1%
When TB diagnosis is 
confirmed
All subjects 
diagnosed with TB
Blood sampling for HIV 
testing - Step 2 (Rapid 
test)
Finger prick or 
at least 2.5 
mL
At screening and when TB 
diagnosis is confirmed
All subjects positive 
at step 15
Blood sampling for 
confirmatory HIV testing 
- Step 3 (ELISA)
At least 2.5 
mL
When initial HIV- test is positive
At screening5
All subjects5
Discordant Rapid 
test results or if no 
Rapid test 
performed6
When TB diagnosis is 
confirmed
At least one positive 
Rapid test or if no 
Rapid test 
performed6
Blood sampling for 
PCR - Step 4
At least 2.5 
mL
When TB diagnosis is 
confirmed
Indeterminate ELISA 
results or no ELISA 
performed and at 
least one positive 
Rapid test6
Blood sampling for CD4 
count
At least 2.5
mL
Whenever a subject is 
diagnosed with TB diagnosis is 
confirmed and confirmed HIV-
positive 
All subjects 
HIV positive subjects 
with TB diagnosis
confirmed
1 Vitamin D levels will be measured at day 0 only.
2 Refer to Section 5.1 for sub-cohort description.
3 The most informative time point for collection of blood samples for RNA expression profiling post dose 2 will be 
determined in a separate study (116777 [TUBERCULOSIS-019]). Depending on the results of this study, the exact 
time point for blood sampling post dose 2 (Visit 6) will be determined. The exact time point will be communicated to the 
investigators appropriately at the latest at study initiation. Additionally, samples for RNA expression profiling must be 
collected at the time of TB diagnosis. 
4 Three sputum samples, preferably taken in the morning, within a one week interval, will be collected whenever a 
subject presents with clinical suspicion of pulmonary TB.
5 HIV testing at screening will only be performed for subjects living in a region with HIV prevalence > 1%.
5 HIV positive subjects at screening will be referred for confirmatory HIV diagnosis/management as per site 
SOPs
6 Only the final conclusive diagnosis is to be recorded in the CRF.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
126
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
127
6.7.3. Laboratory assays
The main laboratory assays will be performed at GSK Biologicals’ laboratory or in a 
laboratory designated by GSK Biologicals “The Collaboration” using standardised 
and/or qualified procedures (Table 9 – Table 14).
Table 11
RNA expression profiling
System
Component
Method
Unit
Laboratory*
Whole blood
RNA expression
Microarray
NA
As designated by 
GSK Biologicals 
“The Collaboration”
*Refer to APPENDIX B for the laboratory addresses.
Table 12
Diagnostic tests for pulmonary TB disease
System
Component
Method
Unit
Laboratory*
Component 
priority 
ranking
Sputum
Mycobacterium 
tuberculosis DNA
Xpert MTB/RIF 
assay
NA
As designated by 
GSK Biologicals 
“The 
Collaboration”
1
Sputum
Mycobacterium 
tuberculosis
Microbiological 
culture
NA
As designated by 
GSK Biologicals 
“The 
Collaboration”
2
*Refer to APPENDIX B for the laboratory addresses.
Table 13
Diagnostic tests for HIV
System
Component
Method
Unit
Laboratory*
Whole Blood or Serum
Anti-HIV antibodies, 
screening step 1, step 2
HIV Rapid Test**
NA
As designated by 
“The Collaboration”
Serum
Anti-HIV antibodies,
screening step 3
ELISA***
NA
As designated by 
GSK Biologicals “The 
Collaboration”
Serum
Anti-HIV antibodies,
screening step 4
Western Blot****
NA
As designated by 
GSK Biologicals “The 
Collaboration”
Whole Blood
HIV RNA,
screening step 4
HIV PCR
NA
As designated by 
“The Collaboration”
Whole blood
CD4 cells
Flow cytometry
Cells/mm
3
As designated by 
GSK Biologicals “The 
Collaboration”
*Refer to APPENDIX B for the laboratory addresses.
**Two different Rapid HIV tests to be used sequentially
***ELISA will be used for initial HIV testing.
****Western Blot will be used for confirmatory HIV testing.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
127
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
128
Table 14
Haematology, Serum Chemistry, Urine tests
System
Component
Method
Scale
Whole blood
Alanine amino transferase
As per laboratory 
standard 
procedures
Investigator’s 
laboratory
Quantitative
Aspartate amino transferase
Creatinine
Bilirubin (total)
Platelets
Leucocytes
Erythrocytes
Haemoglobin
Vitamin D
IFN-
QuantiFERON® TB 
Gold Assay
Qualitative
Urine
-HCG
As per laboratory 
standard 
procedures
Investigator’s 
laboratory
Qualitative
6.7.4.1. Diagnostic assays
Xpert MTB/RIF testing (Cepheid) and microbiological culture will be performed on three 
sputum samples, preferably taken in the morning, within a one week interval, for all 
subjects presenting with clinical suspicion of pulmonary TB throughout the entire study. 
At screening, only Xpert MTB/RIF testing will be performed if the subject presents with 
clinical suspicion of pulmonary TB, to rule out definite pulmonary TB disease.
HIV testing and pre-test counselling will be performed at screening in regions with high 
HIV prevalence (> 1%). HIV positive subjects at screening will be referred for 
confirmatory HIV diagnosis/management as per site SOPs.
[…]
All diagnostic assays will be carried out at the laboratory of the investigator or in a 
laboratory designated by GSK Biologicals “The Collaboration”. Results of diagnostic 
assays will be documented in the subjects’ eCRF.
6.7.4.2. Immunological read-outs
Flow cytometry using a short-term stimulation Intracellular Cytokine Staining (ICS) 
assay on frozen Peripheral Blood Mononuclear Cells (PBMCs) will be used to 
characterise M72-specific CD4+/CD8+ T cells expressing at least two immune markers 
(CD40L and/or IL-2 and/or TNF-and/or IFN-) on Days 0, 7, 30, 37 and 60, and Years 
1, 2 and 3.
[…]
The humoral immune response will be evaluated by assessment of antibody titres to M72 
by specific ELISA on Days 0, 30 and 60, and Years 1, 2 and 3.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
128
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
129
Table 15
Immunological read-outs
Blood sampling time point
Sub-cohort 
Name
No. 
subjects
Component
Type of contact 
and time point
Sampling time 
point
Visit 2 (Day 0)
Pre Vacc
Safety and 
immune sub-
cohort
500
M72-specific T-cells (ICS on PBMCs)
Anti M72 Ab (ELISA on serum)
Visit 3 (Day 7)
Post Vacc 1
M72-specific T-cells (ICS on PBMCs)
Visit 4 (Day 30)
Post Vacc 1
M72-specific T-cells (ICS on PBMCs)
Anti M72 Ab (ELISA on serum)
Visit 5 (Day 37)
Post Vacc 2
M72-specific T-cells (ICS on PBMCs)
Visit 7 (Day 60)
Post Vacc 2
M72-specific T-cells (ICS on PBMCs)
Anti M72 Ab (ELISA on serum)
Visit 8 (Year 1)
LTFU
M72-specific T-cells (ICS on PBMCs)
Anti M72 Ab (ELISA on serum)
Visit 9 (Year 2)
LTFU
M72-specific T-cells (ICS on PBMCs)
Anti M72 Ab (ELISA on serum)
Visit 10 ( Year 3)
LTFU
M72-specific T-cells (ICS on PBMCs)
Anti M72 Ab (ELISA on serum)
6.7.4.3. Haematology/Biochemistry
Serum biochemistry and haematology tests (Hb, PLT, WBC, ALT, AST, bilirubin, 
creatinine) will be performed in the safety and immune sub-cohort on Days 0, 7, 30 and 
37. To characterise the study population, vitamin D levels will be measured at baseline in 
the sub-cohort. The tests will be performed at the laboratory of the investigator’s site or 
in a laboratory designated by GSK Biologicals “The Collaboration”. Results for WBCs, 
haemoglobin, creatinine, ALT, AST, total bilirubin and vitamin D will be recorded in the 
subject’s eCRF or transferred directly to the clinical database.
9.1.4. Clinical laboratories parameters and other abnormal assessments qualifying 
as adverse events or serious adverse events
Table 20
Toxicity grading table for laboratory abnormalities
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening (Grade 4)*
Haematology
Hemoglobin (Female) - gm/dL
11.0 – 12.0
9.5 – 10.9
8.0 – 9.4
< 8.0
Hemoglobin (Female) change 
from baseline value - gm/dL
Any decrease –
1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
Hemoglobin (Male) - gm/dL
12.5 – 13.5
10.5 – 12.4
8.5 – 10.4
< 8.5
Hemoglobin (Male) change 
from baseline value – gm/dL
Any decrease –
1.5
1.6 – 2.0
2.1 – 5.0
> 5.0
11.2. Secondary endpoints
Immunogenicity

Evaluation of CMI responses with respect to components of the study vaccine, in the 
safety and immune sub-cohort.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
129
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
130
Time points: prior to dose 1 (Day 0), post dose 1 (Days 7 and 30) and post dose 2 
(Days 37, 60 and Years 1, 2 and 3).

Evaluation of humoral immune responses with respect to components of the study 
vaccine, in the safety and immune sub-cohort.
Time points: prior to dose 1 (Day 0), post dose 1 (Day 30) and post dose 2 (Day 60, 
Years 1, 2 and 3)
11.3. Tertiary endpoints

Description of RNA expression profile signatures in selected samples as a correlate 
of risk to describe protective and non-protective immune responses after 2 doses of 
M72/AS01E.
Time points: Prior to dose 1 (Day 0) and post dose 2 (post dose 2) and when TB is 
diagnosed.
11.4. Determination of sample size
The two sided Type I error alpha is divided as 0.0002 0.001 and 0.0498 0.049 at interim 
and final analysis, respectively.
The study will only be fully analysed and unblinded early if extremely high efficacy is 
observed at the interim analysis be stopped for efficacy if extremely high efficacy is 
observed at the interim analysis. Therefore a very small alpha is used for the IA.
11.8. Analysis of efficacy
The lower limit of the 99.9899.9% two-sided confidence interval for the VE against first 
occurrence of definite pulmonary TB disease, meeting the first case definition, is above 
0% (this corresponds to a two-sided alpha of 0.020.1%).
The lower limit of the 95.0295.1% two-sided confidence interval for the VE against first 
occurrence of definite pulmonary TB disease, meeting the first case definition is above 
0% (this corresponds to a two-sided alpha of 4.984.9%).
The lower limit of the 95.0295.1% two-sided confidence interval (CI) for the VE against 
first occurrence of Definite Xpert MTB/Rif positive pulmonary TB disease not associated 
with HIV-infection, meeting the second case definition, is above 0%.
11.10. Analysis of safety

Injection site swelling and redness will be analysed using a 3-grade evaluation 
system [0 mm (grade 0); > 0 to 20 mm (grade 1); > 20 to 50 mm (grade 2); > 50 mm 
(grade 3)].
11.12.2. Statistical considerations for interim analyses
The analysis will be performed by a statistician external to the investigator group and 
GSK Biologicals “The Collaboration” (i.e. from a contract research organisation). The 
clinical team within GSK Biologicals and Aeras, all participating subjects, study site and 
GSK personnel directly involved in the conduct of the trial will remain blinded to the 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
130
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
131
randomisation codes. The GSK statistician (and other GSK personnel directly involved in 
the conduct of the trial) will not have access to the randomisation list and serology data.
The efficacy results at interim analysis will be looked at by the IDMC in closed session 
(with prohibited attendance by any member of GSK and Aeras and by any person 
involved in the conduct of the study).
12.1 Remote Data Entry instructions
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor designated by 
“The Collaboration” at the study site, omissions or inconsistencies detected by 
subsequent eCRF review may necessitate clarification or correction of omissions or 
inconsistencies with documentation and approval by the investigator or appropriately 
qualified designee. In all cases, the investigator remains accountable for the study data.
12.2. Study Monitoring by GSK Biologicals “The Collaboration”
GSK and “The Collaboration” will monitor the study to verify that, amongst others, the: 
[…]
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK “The Collaboration” procedures.
12.3. Record retention
GSK “The Collaboration” will inform the investigator/institution of the time period for 
retaining these records to comply with all applicable regulatory requirements. However, 
the investigator/institution should seek the written approval of the sponsor before 
proceeding with the disposal of these records. The minimum retention time will meet the 
strictest standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures; otherwise, 
the minimum retention period will default to 15 years. 
The investigator/institution must notify GSK “The Collaboration” of any changes in the 
archival arrangements, including, but not limited to archival at an off-site facility, transfer 
of ownership of the records in the event the investigator leaves the site.
12.4. Quality assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK or 
“The Collaboration” may conduct a quality assurance audit. Regulatory agencies may 
also conduct a regulatory inspection of this study. Such audits/inspections can occur at 
any time during or after completion of the study. If an audit or inspection occurs, the 
investigator and institution agree to allow the auditor/inspector direct access to all 
relevant documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
131
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
132
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 3
eTrack study number 
and Abbreviated Title:
115616 (TUBERCULOSIS-018)
Amendment number:
Amendment 3
Amendment date:
11 December 2012
Co-ordinating author:
, Project Manager Scientific Writing, XPE 
Pharma&Science, contractor for GSK Biologicals
Rationale/background for changes:
!
An additional country (Zambia) was added to the study. In order to avoid protocol 
amendments in the future whenever a new country is added, all country 
specificities were removed from the protocol. 
!
The interval between the screening visit and the first vaccination visit was 
decreased to allow subjects to be enrolled and screened on the same day as the first 
vaccination.
!
Additional small changes were made to align with the eCRF and available 
statistical methods.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Synopsis:
Rationale for the study and study design
This Phase IIb study is designed to evaluate the protective efficacy of the M72/AS01E
candidate tuberculosis vaccine against definite pulmonary TB disease not associated with 
HIV-infection, versus placebo, following 2 injections given one month apart. The 
protective efficacy will be evaluated in adults living in a TB endemic region (India, South 
Africa and Kenya) aged 18-50 years, i.e. in an age range where the incidence of 
tuberculosis is high.
Section 1.3.2 Rational for the study design
This study is designed to evaluate the protective efficacy of the M72/AS01E candidate 
tuberculosis vaccine against definite pulmonary TB disease, versus placebo, following 2 
injections given one month apart. The protective efficacy will be evaluated in adults 
living in a TB endemic region (India, South Africa and Kenya) aged 18-50 years, i.e. in 
an age range where the incidence of tuberculosis is high (Figure 1).

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
132
29-JAN-2014
PPD

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
133
Section 5.1
Number of subjects/centres
The study will be conducted in India, Kenya and South Africa multiple TB endemic 
countries, in multiple enrolling centres. The study centres will be experienced in 
detecting TB and have access to TB treatment or have an established referral option for 
TB patients and HIV-infected individuals.
There will be one sub-cohort for safety/reactogenicity and immunogenicity. A maximum 
of 500 eligible subjects from selected centres in India and South Africa will be included 
in this safety and immune sub-cohort (Table 4). The subjects included in the safety and 
immune sub-cohort will be equally distributed between Africa and India.  
Table 4
Sub-cohorts 
Sub-cohort name
Description
Estimated number 
of subjects
Safety and immune 
sub-cohort
Safety parameters for this sub-cohort will be collected as follows:

Solicited AEs will be collected for 7 days (day of vaccination and 
6 subsequent days) following vaccination.

Serum biochemistry/haematology values will be measured at 
Days 0, 7, 30, and 37.
Approximately Up 
to 450
Immunogenicity:

Humoral immunogenicity will be evaluated by measuring M72-
specific IgGs at Days 0 and 60 and Years 1, 2 and 3.

CMI will be evaluated by measuring M72-specific CD4+ and 
CD8+ T cells expressing at least 2 immune markers (CD40-L 
and/or IFN-γ and/or IL-2 and/or TNF-) at Days 0 and 60 and 
Years 1, 2 and 3.

The QuantiFERON status of subjects will be determined at 
Day 0 and Years 1, 2 and 3.
Section 6.2.3 Allocation of subjects to assay subsets
Approximately 500 subjects will be included in the safety and immune sub-cohort. These 
subjects will be enrolled at selected centres in India and South Africa. Subjects included 
in the safety and immune sub-cohort will be equally distributed between Africa and India.
Blood sampling and safety assessment will be performed as described in Table 4.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
133
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
134
Section 6.5
Outline of study procedures
Table 5
List of study procedures 
Visit 1 
Screening visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8
Contact 5, 
6, 7, 8, 9
Visit 8
Contact 10, 
11, 12, 13, 14
Visit 9
Time point(s)
D-30
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
All subjects 
Informed consent
●
Check inclusion/exclusion 
criteria
●
●
Collect demographic data
●
Medical history
●
●
Physical examination
●
History-directed physical 
examination
O
O
O
O
O
O
Resting vital signs
O
O
O
HIV testing3 (up to 2.5 
mL/test)
●
Record weight4
●
●
●
●
Documentation of history of 
BCG vaccination/presence 
of scar
●
Pregnancy test (-HCG 
urine)
●
●
●
Study group and treatment 
number allocation
O
Treatment number allocation 
for second dose
O
Vaccination 
●
●
Recording of administered 
treatment number
●
●
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
134
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
135
Visit 1 
Screening visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8
Contact 5, 
6, 7, 8, 9
Visit 8
Contact 10, 
11, 12, 13, 14
Visit 9
Time point(s)
D-30
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Check contraindications to 
subsequent vaccination
●
●
Recording concomitant 
medication/vaccination
●
●
●
●
●
●
●
●
●
●
●
●
●
Recording intercurrent 
medical condition
●
●
●
●
●
●
●
●
●
●
●
●
Distribution of diary cards
O
O
Return of diary cards
O
O
Recording of unsolicited AEs 
●
●
●
●
●
●
Pre-vaccination assessment 
(including temperature)
●
●
Blood sampling for RNA 
expression profiling (2.5 
mL)5
●
●
Reporting SAEs
●6
●
●
●
●
●
●
●7
●6
●6
●6
●6
●6
Reporting pIMDs
●
●
●
●
●
●
●8
Reporting pregnancy
●
●
●
●
●
●
●8
Diagnostic procedures for 
suspected pulmonary TB
●
●
●
●
●
●
●
●
●
●
●
Documentation of TB cases
●
●
●
●
●
●
●
●
●
●
●
Safety and immune sub-
cohort
Measuring Vitamin D
●
Recording of solicited AEs
●
●
●
●
CBC (Hb, PLT and WBC), 
ALT, AST, creatinine, 
bilirubin (8 mL)
●
●
●
●
Blood sampling for CMI (
2.5 mL)
●
●
●
●
●
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
135
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
136
Visit 1 
Screening visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8
Contact 5, 
6, 7, 8, 9
Visit 8
Contact 10, 
11, 12, 13, 14
Visit 9
Time point(s)
D-30
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Blood sampling for humoral 
immunogenicity (2 mL)
●
●
●
●
●
●
●
Study conclusions for all 
subjects
●
Note: The double border at Month 36 indicates the final analyses which will be performed on all data obtained up to month 36.
Pre V: Pre Vaccination; V: Vaccination; Post V: Post Vaccination
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
1 Only subjects in the safety and immune sub-cohort need to come for this visit.
2 The most informative time point for collection of blood samples for RNA expression profiling post dose 2 will be determined. The exact time point will be communicated to the 
investigators appropriately at the latest at study initiation.
3 HIV testing and pre-test counselling will be performed at screening in areas were HIV-prevalence > 1%, according to the procedures detailed in Table 9.
4 Weight also needs to be recorded whenever there is suspicion of TB disease is confirmed (definite and clinical).
5 Samples for RNA expression profiling will also be taken at the time of TB diagnosis.
6 Only SAEs related to study participation or concurrent GSK medication/vaccine.
7 SAEs not related to study participation or concurrent GSK medication/vaccines will be recorded until 6 months post dose 2 (M7).
8 To be recorded until 6 months post dose 2 (M7).
9 Sputum samples for Xpert MTB/RIF testing and microbiological culture will be taken throughout the study if a subject presents with clinical suspicion of pulmonary TB disease. Three 
sputum samples, preferably taken in the morning and within one week, must be collected. Additionally, when a subject is diagnosed with TB, HIV testing must be performed according 
to the procedures detailed in Table 9. Up to 2.5mL of blood will be collected per test. If the subject is confirmed HIV-positive, blood samples must be taken (2.5 mL) to measure CD4 
counts.
10 Documentation of TB cases will be done throughout the study, starting at Visit 3 (Day 7); this includes documentation of cases during active and passive follow-up and monitoring of 
medical facilities and pharmacies.
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
136
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
137
Table 6
Intervals between study visits for all subjects
Interval
Allowed interval1
Visit 1 - Visit 2
30 days - 10 days
Visit 2 - Visit 4
26 days - 35 days
Visit 4 - Visit 6
1 days - 25 days 2
Visit 4 - Visit 7
14 days - 35 days
Visit 4 - Visit 8
10 months - 12 months
Visit 4 - Visit 9
22 months -24 months
Visit 4 - Visit 10
34 months - 36 months
Visit n – next contact
6 weeks – 12 weeks
Contact n – contact n+1
6 weeks – 12 weeks
Section 11.8
Analysis of efficacy
The ATP cohort for efficacy will be used for the primary analysis of efficacy. If the 
percentage of enrolled subjects excluded from the ATP cohort for analysis of efficacy is 
more than 5%, a second analysis based on the TVC will be performed to complement the 
primary analysis.
As a primary analysis, vaccine efficacy will be estimated using a frequentist approach. In 
this analysis, vaccine efficacy is defined as 1-RR where RR is the Poisson rate ratio. The 
rate in the vaccine group is equal to the number of cases in the vaccine group divided by 
the follow-up time. The rate in the control group is defined the same way. CIs and p-
values will be calculated using the exact method implemented in the Poisson procedure 
of the StatXact package provided by Cytel. This method is also available in proc
genmod when using the exact option. 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
137
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
138
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 4
eTrack study number 
and Abbreviated Title
115616 (TUBERCULOSIS-018)
Amendment number:
Amendment 4
Amendment date:
29 March 2013
Co-ordinating author:
, Project Manager Scientific Writing, XPE 
Pharma&Science, contractor for GSK Biologicals
Rationale/background for changes: 
The study was initially designed to evaluate the efficacy of two doses of the 
M72/AS01E candidate vaccine against definite pulmonary TB disease in multiple 
countries in Africa and in India to obtain initial efficacy data in these populations. 
However, to increase the feasibility and reduce the logistical burden and complexity, 
the study was re-evaluated to include multiple countries in Africa only. As the 
incidence rate in Africa (overall incidence rate: 262 per 100.000 population1) is 
significantly higher as compared to India (incidence rate: 181 per 100.000 population), 
a significantly lower number of subjects (4500 versus 7000) will be needed to evaluate 
the vaccine efficacy (VE).
The sample size was recalculated based on the logrank test for comparison of time to 
first diagnosis of definite pulmonary TB disease: assuming 80% power for a true VE of 
70% and a two-sided 5% significance level, 27 cases of definite pulmonary TB disease, 
meeting the first case definition would be required instead of 28, as previously 
determined using the Poisson rate ratio. To obtain these 27 cases, using updated 
estimated yearly attack rates in the control group (Africa only: 0.35% instead of Africa 
and India combined: 0.29%), a follow-up of 3 years and a loss of follow-up time of 
12% due to drop out, 4500 enrolled subjects will be needed. 
The vaccine efficacy defined as 1-estimated hazard ratio and associated 95% CIs and 
Wald p value will be derived using a Cox proportional hazards regression model.
Initially, the number of subjects in the safety and immune sub-cohort was set at 
500, equally distributed between India and Africa in order to bridge the immune 
responses between these populations. As India will no longer be included in the 
study and the total number of subjects has decreased from 7000 to 4500, the 
number of subjects to be included in the safety and immune sub-cohort decreased 
from 500 to 450 subjects (225 subjects in each treatment group). Subjects from 
multiple countries (2 or 3) will be included in the sub-cohort to explore potential 
differences in vaccine take between different countries. Up to 150 subjects 
enrolled in each contributing country (if 3 contributing countries) or up to 225 
                                                
1 World Health Organisation (WHO). Global Tuberculosis Report, 2012
http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
138
29-JAN-2014
PPD

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
139
subjects enrolled in each contributing country (if 2 contributing countries) will be 
included in the safety and immune sub-cohort. Assuming a standard deviation of 
log10(GMT or GM frequency of CD4 T cells expressing at least 2 immune 
markers) of 0.40, as observed in previous studies, a precision for the 95 % CI for 
log10(GMT or median frequency of CD4 T cells expressing at least 2 immune 
markers) of 0.052 or 0.092 will be obtained for a total samples size of 225 
subjects vaccinated with M72/AS01E or 75 subjects vaccinated with 
M72/AS01E/country respectively.
Cell-mediated immune responses will be evaluated in whole blood samples 
instead of peripheral blood mononuclear cells (PBMCs), excluding the need for 
PBMC separation at the investigator’s laboratory or central laboratory and 
decreasing the volume of blood to be collected while obtaining the same results.
In addition, this study offers the opportunity to evaluate whether the M72/AS01E 
candidate vaccine might also provide protection against Mycobacterium 
tuberculosis (Mtb) infection. Mtb complex infection, whether tuberculosis 
disease, latent TB infection or past TB infection, can be detected by interferon-
gamma release assays (IGRAs), such as the QuantiFERON® TB Gold (QFTG) 
assay (Cellestis), by measuring IFN-release by memory T cells in response to 
Mtb antigens. The QuantiFERON® TB Gold In Tube method uses peptide 
cocktails covering the early secretory antigen target-6 (ESAT-6),culture filtrate 
protein-10 (CFP-10) and TB 7.7 protein sequences to stimulate T cell 
lymphocytes. As these proteins are absent from all BCG strains, the test is not 
confounded by previous BCG vaccination nor is it confounded by exposure to 
most environmental mycobacteria. 
Although yearly QFTG testing is planned for all subjects included in the safety 
and immune sub-cohort (N=450) to estimate the exposure to TB during the study,
QFTG testing will also be performed at baseline for all subjects ,at the end of the 
study (Year 3) for all subjects QFTG-negative at baseline to evaluate the 
protective efficacy of the candidate vaccine against Mtb infection, as measured 
by QFTG conversion. In addition QFTG testing will be performed whenever a 
subject is diagnosed with TB disease. 
To avoid trial progression with a vaccine candidate with very low efficacy, an interim 
efficacy analysis for futility is planned after approximately 10 Xpert MTB/Rif positive 
pulmonary TB cases in confirmed HIV-negative subjects (approximately 40% of the 
target events) have accumulated in the modified Total Vaccinated Cohort (TVC) for 
interim efficacy analysis at least 1 month post dose two. The modified TVC for interim 
efficacy will include all subjects who received two vaccine doses according to protocol 
and did not present with TB disease, according to any case definition, before 
completion of the vaccination phase (up to 1 month post dose 2) without randomisation 
failure and without wrong replacement. The interim analysis for futility will be 
performed by the Independent Data Monitoring Committee (IDMC) statistician and 
stopping rules for futility will be defined in the statistical analysis plan for interim 
analysis. If the study is stopped for futility, all subjects will be followed up until
completion of the safety follow-up (up to 6 months post dose 2). An interim analysis 
after accrual of half of the total number of cases is therefore no longer foreseen.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
139
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
140
Other changes to the protocol include:

Names and addresses of laboratories involved in the conduct of the study 
(previously not identified), are included.

History of household contacts, smoking and diabetes will be recorded at screening
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Synopsis: Rationale for the study design

Rationale for the study design
A sub-cohort of subjects will be selected for specific follow-up for safety (solicited 
adverse events [AE] and selected Biochemistry and Complete Blood Count [CBC]) and 
immunogenicity. Unsolicited AEs, serious adverse events (SAEs), potential immune-
mediated diseases (pIMDs), AEs leading to withdrawal and pregnancies will be recorded 
for all subjects. An IFN-positive T cell response induced by past or present Mtb 
infection, as measured by the QuantiFERON® TB Gold (QFTG) assay (Cellestis), will 
be evaluated at baseline for all subjects, at study end (Year 3) for all subjects QFTG-
negative at baseline and yearly for subjects in the safety and immune sub-cohort. In 
addition, a QFTG assay will be performed whenever a subject is diagnosed with TB 
disease.
Synopsis: Objectives
Primary
Success criterion:
The lower limit of the 95.1% two-sided confidence interval (CI) for the VE (using a Cox 
regression model) against first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the first case definition, is above 0%.
Secondary
If the primary objective is met, this secondary objective will be analysed with the 
following success criterion:
The lower limit of the 95.1% two-sided confidence interval (CI) for the VE (using a Cox 
regression model) against first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the first case definition, is above 0%.
Tertiary

To evaluate the protective efficacy of two doses of the M72/AS01E candidate 
vaccine against Mtb infection, as measured by QFTG conversion.
*QFTG conversion is defined as the change from a negative QFTG test result (value 
below the cut off for IFN-concentration) to a positive QFTG test result (value at or 
above the cut off for IFN-concentration) in two serial samples.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
140
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
141
Synopsis Table 1
Study groups and epochs foreseen in the study
Study groups
Number of 
subjects
Age (Min/Max)
Epoch 001
M72AS01
3500 2250
18 - 50 years
x
Control
3500 2250
18 - 50 years
x
Synopsis: Sampling schedule

Blood samples will be collected in the safety and immune sub-cohort for 
evaluation of biochemistry/haematology parameters (Days 0, 7, 30 and 37), CMI 
responses (Days 0, 60 and Years 1, 2 and 3) and humoral immune responses
(Days 0, 60 and Years 1, 2 and 3). and QuantiFERON status

Blood samples will be collected for QFTG testing at baseline (Day 0) for all 
subjects, at study end (Year 3) for all subjects QFTG-negative at baseline and 
yearly for subjects included in the safety and immune sub-cohort.

Blood samples for RNA expression profiling will be collected from all subjects 
(Days 0 and post dose 2and when TB is diagnosed) 

Whenever a subject is diagnosed with TB disease, blood samples will be 
collected for HIV testing, mRNA expression profiling and QFTG testing. In 
addition, if a subject is HIV-positive, blood samples will be collected to 
determine CD4 cell counts.
Synopsis: safety monitoring
an Independent Data Monitoring Committee (IDMC), operating under a charter, will be 
constituted for this study to oversee the study. They will perform safety reviews three 
times in the first year of enrolment and twice a year, or more frequently if deemed 
necessary on an ongoing basis for the duration of the study and evaluate the interim 
efficacy analysis
Synopsis: Number of subjects
Approximately 70004500
Synopsis: Secondary endpoints 
Immunogenicity

Evaluation of CMI responses with respect to components of the study vaccine, in the 
safety and immune sub-cohort:

Determined by the frequency of M72-specific CD4+/CD8+ T cells per million 
cells identified after in vitro stimulation, as expressing at least 2 immune markers 
among CD40L, IL-2, IFN-and TNF-.

Determined by the frequency of M72-specific CD4+/CD8+ T cells per million 
cells identified after in vitro stimulation, as expressing any combination of 
immune markers among CD40L, IL-2, IFN-and TNF-.
Time points: prior to dose 1 (Day 0) and post dose 2 (Day 60, Years 1, 2 and 3)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
141
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
142
Safety

Occurrence of grade 2 haematological and biochemical levels at:
Days 0, 7, 30 and 37
Synopsis: Tertiary endpoints

Evaluation of CMI responses with respect to components of the study vaccine, in 
the safety and immune sub-cohort:

Determined by the frequency of M72-specific CD4+/CD8+ T cells per million 
cells identified after in vitro stimulation, as expressing any combination of 
immune markers among CD40L, IL-2, IFN-and TNF-.
Time points: prior to dose 1 (Day 0) and post dose 2 (Day 60 and Years 1, 2 and 3)

QFTG test result. 
Time points: prior to dose 1 (Day 0), post dose 2 (Year 3)
LIST OF ABBREVIATIONS:
IGRA
Interferon-Gamma Release Assay
QFTG
QuantiFERON® TB Gold
GLOSSARY OF TERMS
QFTG conversion
The change from a negative QFTG test result (value 
below the cut off for IFN-concentration) to a positive 
QFTG test result (value at or above the cut off for IFN-
concentration) in two serial samples.
The QFTG assay detects memory T cell responses 
against Mtb as a surrogate for exposure to/infection 
with Mtb. The QFTG does not directly measure the 
presence of Mtb. The QFTG does not indicate whether 
the immune response of a subject is able to eliminate the 
bacteria or whether Mtb is latently present
Section 1.3.2 Rational for the study design
A sub-cohort of subjects will be selected for specific follow-up for safety (solicited 
adverse events (AE) and selected Biochemistry and Complete Blood Count [CBC]) and
immunogenicity. Unsolicited AEs, serious adverse events (SAEs), potential immune-
mediated diseases (pIMDs), AEs leading to withdrawal and pregnancies will be recorded 
for all subjects. An IFN-positive T cell response induced by past or present Mtb 
infection, as measured by the QuantiFERON® TB Gold (QFTG) assay (Cellestis), will 
be evaluated at baseline for all subjects, at study end (Year 3) for all subjects QFTG-
negative at baseline and yearly in safety and immune the sub-cohort. In addition, a 
QFTG assay will be performed whenever a subject is diagnosed with TB disease.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
142
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
143
Section 2.1
Primary Objective
Success criterion to be used for the primary objective: 
The lower limit of the 95.1% two-sided confidence interval (CI) for the VE against 
first occurrence of Definite pulmonary TB disease not associated with HIV-infection, 
meeting the first case definition, is above 0%
Section 2.2
Secondary Objectives
Efficacy:
If the primary objective is met, this secondary objective will be analysed using the 
following success criterion:
The lower limit of the 95.1% two-sided confidence interval (CI) for the VE against 
first occurrence of Definite pulmonary TB disease not associated with HIV-infection, 
meeting the first case definition, is above 0%
Section 2.3
Tertiary Objectives

To evaluate the protective efficacy of two doses of the M72/AS01E candidate 
vaccine against Mtb infection, as measured by QFTG conversion.
…
Refer to the GLOSSARY OF TERMS for a definition of QFTG conversion.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
143
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
144
Section 3
Study design overview
Figure 2
Overview of the study design
The following figure:
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
144
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
145
Was replaced by:

Duration of the study: the duration of the study will be approximately 37 months
for each subject from screening up to end of efficacy follow-up.
Table 1
Study groups and epochs foreseen in the study
Study Groups
Number of 
subjects
Age (Min - Max) 
(age unit)
Epoch 001
M72AS01
3500 2250
18 - 50 years
x
Control
35002250
18 - 50 years
x

Sampling schedule: 

Blood samples will be collected in the safety and immune sub-cohort for 
evaluation of biochemistry/haematology parameters (Days 0, 7, 30 and 37), CMI 
responses (Days 0, 60 and Years 1, 2 and 3) and humoral immune responses 
(Days 0, 60 and Years 1, 2 and 3) and QuantiFERON status.

Blood samples will be collected for QFTG testing at baseline (Day 0) for all 
subjects, at study end (Year 3) for all subjects QFTG-negative at baseline and 
yearly for subjects included in the safety and immune sub-cohort.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
145
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
146

Blood samples for RNA expression profiling will be collected from all subjects 
at predefined time points (Days 0 and Day 44*)and whenever a subject is 
diagnosed with TB disease .

Whenever a subject is diagnosed with TB disease, blood samples will be 
collected for HIV testing, mRNA expression profiling and QFTG testing. In 
addition, if a subject is HIV-positive, blood samples will be collected to 
determine CD4 cell counts.
Section 5.1
Number of subjects/centres
Approximately 70004500 men and women aged 18-50 years will be enrolled in the study. 
Enrolment will be terminated when target number of subjects is reached.
The study will be conducted in multiple TB endemic countries, in multiple enrolling 
centres. The study centres will be experienced in detecting TB and have access to TB 
treatment or have an established referral option for TB patients and HIV-infected 
individuals.
There will be one sub-cohort for safety/reactogenicity, and immunogenicity. A maximum
Approximately of 500 450 eligible subjects from selected centres in multiple countries (2 
or 3) will be included in this safety and immune sub-cohort (Table 4). Up to 150 enrolled 
in each contributing country (if 3 contributing countries) or up to 225 subjects enrolled 
in each contributing country (if 2 contributing countries) may be included in the safety 
and immune sub-cohort.
To ensure the gender of the study population is equally distributed between females and 
males, a cap has been put on the number of subjects per gender to be enrolled. A 
maximum of 60% of subjects from the same gender will be enrolled in the study and 
enrolment of females/males will be stopped at approximately 4200 2700 subjects of any 
gender maximum.
Table 4
Sub-cohorts
Sub-cohort name
Description of additional activities
Estimated number 
of subjects
Safety and immune 
sub-cohort
Safety parameters for this sub-cohort will be collected as follows:

Solicited AEs will be collected for 7 days (day of vaccination and 
6 subsequent days) following vaccination.

Serum biochemistry/haematology values will be measured at 
Days 0, 7, 30, and 37.
Approximately Up 
to 500450
Immunogenicity:

Humoral immunogenicity will be evaluated by measuring M72-
specific IgGs at Days 0 and 60 and Years 1, 2 and 3.

CMI will be evaluated by measuring M72-specific CD4+ and 
CD8+ T cells expressing at least 2 immune markers (CD40-L 
and/or IFN-γ and/or IL-2 and/or TNF-) at Days 0 and 60 and 
Years 1, 2 and 3.

The QuantiFERON status of subjects will be determined at 
Day 0 and Years 1, 2 and 3.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
146
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
147
Section 6.2.2.2.1
Study group and treatment number allocation
The target will be to enrol approximately 7000 4500 eligible subjects who will be 
randomly assigned to two study groups in a 1:1 ratio (approximately 3500 2250 subjects 
in each group).
Allocation of the subject to a study group at the investigator site will be performed using 
a randomisation system on internet (SBIR). The randomisation algorithm will use a 
minimisation procedure accounting for:

Gender: a maximum of 4200 2700 females/males will be recruited. 

TB disease categorised as history or no history of TB disease.
Section 6.2.3 Allocation of subjects to assay subsets
Approximately 500 450 subjects will be included in the safety and immune sub-cohort. 
These subjects will be enrolled at selected centres. Blood sampling and safety assessment 
will be performed as described in Table 4. Distribution of subjects in the sub-cohort is 
presented in Table 5.
Table 5
Distribution of subjects in the sub-cohort
Sub-cohort
Treatment group
N to be enrolled
Safety and immune sub-cohort
M72AS01
Approximately 225
Control
Approximately 225
Section 6.4.2 Diagnostic procedures for the detection of suspected pulmonary TB
Additionally if TB is confirmed a serological test (and pre-test counselling) for HIV-
infection must be performed to rule out HIV co-infection and a blood sample for RNA 
expression profiling and QFTG testing must be taken. If the subject is HIV-positive, 
additional testing must be performed to measure CD4 cell counts.
Results of HIV testing, including CD4 cell counts if applicable, and QFTG testing must 
be recorded in the subjects’ eCRF.
Section 6.4.3 Diagnostic procedures for suspected extra-pulmonary TB
Additionally, if extra-pulmonary TB is confirmed, a serological test (and pre-test 
counselling) for HIV-infection must be performed to rule out HIV co-infection and a 
blood sample for RNA expression profiling and QFTG testing must be taken. If the 
subject is HIV-positive, additional testing must be performed to measure CD4 cell 
counts.
Results of HIV testing, including CD4 cell counts, if applicable, and QFTG testing must 
be recorded in the subjects’ eCRF.
Section 6.4.5.2
Independent Data Monitoring Committee
In order to ensure the safety of the subjects during the entire study period, an Independent 
Data Monitoring Committee (IDMC) will be appointed to monitor the safety and 
tolerability of the vaccine/placebo administered in the trial and, if necessary, make 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
147
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
148
recommendations to the sponsor concerning the modification or termination of the trial. 
The IDMC will perform safety reviews three times in the first year and twice a year or 
more frequently if deemed necessary on an ongoing basis during the study period.
(Amended 26 March 2013)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
148
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
149
Section 6.5
Outline of study procedures
Table 6
List of study procedures
Visit 1 
Screening visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8
Contact 5, 
6, 7, 8, 9
Visit 9
Contact 10, 
11, 12, 13, 14
Visit 10
Time point(s)
D-30
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
All subjects 
Informed consent
●
Check inclusion/exclusion 
criteria
●
●
Collect demographic data
●
Medical history
●
●
Physical examination
●
History-directed physical 
examination
O
O
O
O
O
O
Resting vital signs
O
O
O
HIV testing3 (up to 2.5 
mL/test)
●
Record weight4
●
●
●
●
Documentation of history of 
BCG vaccination/presence 
of scar
●
Documentation of history 
of TB household contacts
●
Pregnancy test (-HCG 
urine)
●
●
●
Study group and treatment 
number allocation
O
Treatment number allocation 
for second dose
O
Vaccination 
●
●
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
149
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
150
Visit 1 
Screening visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8
Contact 5, 
6, 7, 8, 9
Visit 9
Contact 10, 
11, 12, 13, 14
Visit 10
Time point(s)
D-30
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Recording of administered 
treatment number
●
●
Check contraindications to 
subsequent vaccination
●
●
Recording concomitant 
medication/vaccination
●
●
●
●
●
●
●
●
●
●
●
●
●
Recording intercurrent 
medical condition
●
●
●
●
●
●
●
●
●
●
●
●
Distribution of diary cards
O
O
Return of diary cards
O
O
Recording of unsolicited AEs 
●
●
●
●
●
●
Pre-vaccination assessment 
(including temperature)
●
●
Blood sampling for RNA 
expression profiling (2.5 
mL)5
●
●
Blood sampling for IGRA 
conversion(3 mL)6
●
●7
Reporting SAEs
●68
●
●
●
●
●
●
●79
●68
●68
●68
●68
●68
Reporting pIMDs
●
●
●
●
●
●
●810
Reporting pregnancy
●
●
●
●
●
●
●8
Diagnostic procedures for 
suspected pulmonary TB911
●
●
●
●
●
●
●
●
●
●
●
Documentation of TB 
cases1012
●
●
●
●
●
●
●
●
●
●
●
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
150
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
151
Visit 1 
Screening visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 7
Contact 1, 
2, 3 and 4
Visit 8
Contact 5, 
6, 7, 8, 9
Visit 9
Contact 10, 
11, 12, 13, 14
Visit 10
Time point(s)
D-30
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Safety and immune sub-
cohort
Measuring Vitamin D
●
Recording of solicited AEs
●
●
●
●
CBC (Hb, PLT and WBC), 
ALT, AST, creatinine, 
bilirubin (8 mL)
●
●
●
●
Blood sampling for CMI (
18 2.5 mL)
●
●
●
●
●
Blood sampling for humoral 
immunogenicity (2 mL)
●
●
●
●
●
Blood sampling for IGRA 
conversion(3 mL) 
●
●
●
●
Study conclusions for all 
subjects
●
Note: The double border at Month 36 indicates the final analyses which will be performed on all data obtained up to month 36.
Pre V: Pre Vaccination; V: Vaccination; Post V: Post Vaccination
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
1 Only subjects in the safety and immune sub-cohort need to come for this visit.
2 The most informative time point for collection of blood samples for RNA expression profiling post dose 2 will be determined. The exact time point will be communicated to the 
investigators appropriately at the latest at study initiation.
3 HIV testing and pre-test counselling will be performed at screening in areas were HIV-prevalence > 1%, according to the procedures detailed in Table 9.
4 Weight also needs to be recorded whenever there is suspicion of TB disease.
5 Samples for RNA expression profiling will also be taken at the time of TB diagnosis.
6 Samples for QFTG testing will also be taken at the time of TB diagnosis.
7 Only for subjects QFTG-negative at baseline.
68 Only SAEs related to study participation or concurrent GSK medication/vaccine.
79 SAEs not related to study participation or concurrent GSK medication/vaccines will be recorded until 6 months post dose 2 (M7). 
810 To be recorded until 6 months post dose 2 (M7). 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
151
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
152
911 Sputum samples for Xpert MTB/RIF testing and microbiological culture will be taken throughout the study if a subject presents with clinical suspicion of pulmonary TB disease. 
Three sputum samples, preferably taken in the morning and within one week, must be collected. Additionally, when a subject is diagnosed with TB, HIV testing must be performed 
according to the procedures detailed in Table 9. Up to ( 2.5mL of blood will be collected per test. If the subject is confirmed HIV-positive, blood samples must be taken (2.5 mL) to 
measure CD4 counts.
1012 Documentation of TB cases will be done throughout the study, starting at Visit 3 (Day 7); this includes documentation of cases during active and passive follow-up and monitoring 
of medical facilities and pharmacies.
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
152
29-JAN-2014

CONFIDENTIAL
29-JAN-2014
153
Section 6.6.4 Collect history of TB household contacts
Question the subject about recent exposure (within the last 12 months) to a person 
(household contact) diagnosed with and/or treated for pulmonary TB disease.
Record history of TB household contacts in the subject’s eCRF.
Section 6.6.5 Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF. In particular, chronic pulmonary 
conditions (such as COPD, silicosis), history of smoking and diabetes* must be recorded
(* type I diabetes is an exclusion criterion).
Section 6.6.12.1
Blood sampling for safety, or immune response assessments 
and QFTG status
As specified in the List of Study Procedures in Section 6.5 (Table 6), blood samples are 
taken during certain study visits. Refer to the Module on Biospecimen Management in 
the SPM and lab manual for detailed instructions for the collection, handling and 
processing of the samples.

For all subjects included in the safety and immune sub-cohort:

A volume of at least 3 mL of whole blood should be drawn for QFTG testing
QuantiFERON® TB Gold Assay at each predefined time point (Table 9).

A volume of at least 2 mL of whole blood should be drawn for analysis of 
humoral immune responses at each predefined time point (Table 9).

A volume of at least 18 2.5 mL of whole blood should be drawn for analysis of 
cell-mediated immune (CMI) responses at each predefined time point (Table 9).

A volume of at least 8 mL of whole blood should be drawn for tests performed to 
assay for CBC, ALT, AST, bilirubin and creatinine at each predefined time point 
(Table 9). Vitamin D levels will be measured at Day 0 only.

For all subjects:

A volume of at least 2.5 mL of whole blood will be collected directly in a 
Paxgene™Blood RNA Tube providing pure RNA for accurate detection and 
quantification of RNA expression profiles (“transcriptomics”) at each predefined 
time point* (Table 9).

At screening, HIV testing must be performed according to the procedures 
detailed in Table 9 in regions with high HIV prevalence (> 1%). Up to 
approximately 2.5 mL of blood will be collected for each test. 

A volume of at least 3 mL of whole blood should be drawn for QFTG testing at 
each predefined time point** (Table 9)
*Blood sampling for RNA expression profiling is planned for Day 0 (Visit 2) and 
Visit 6 (post dose 2). The most informative time point for collecting whole blood 
samples for RNA expression profiling post dose 2 will be determined. The exact 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
153
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
154
time point will be communicated to the Investigators appropriately at the latest at 
study initiation.
**At study end (Year 3) QFTG testing will only be performed for all subjects 
QFTG-negative at baseline.

Whenever a subject is diagnosed with TB disease:

When a subject is diagnosed with TB disease, HIV testing must be performed 
according to the procedures detailed in Table 9. Up to approximately 2.5 mL of 
blood will be collected for each test. Additionally, if HIV is confirmed, at least 
2.5 mL of blood will be collected to measure CD4 counts. 

A volume of at least 2.5 mL of whole blood will be collected directly in a 
Paxgene™Blood RNA Tube providing pure RNA for accurate detection and 
quantification of RNA expression profiles (“transcriptomics”).

A volume of at least 3 mL of whole blood should be drawn for QFTG testing.
Section 6.6.12.2 Sputum sample collection for TB diagnosis
Refer to the Module on Biospecimen Management in the SPM and lab manual for 
detailed instructions for the induction of sputum, collection, handling and processing of 
the samples.
Section 6.6.13
TB disease capture
Additionally, medical facilities and Pharmacists awareness (if applicable) and 
surveillance will be put in place in the study area to ensure that TB disease cases 
occurring in study participants are captured. All Medical facilities and Pharmacists in the 
study area will be informed of the trial. A team of study personnel/health workers will 
visit the medical facilities monthly to identify study subjects admitted to or cared for at 
the hospitals for TB. Relevant staff at the medical facilities will be advised to contact the 
study personnel for each TB case to ensure that all cases are captured.
Section 6.6.16
Recording of AEs, SAEs, pregnancies and pIMDs

At each vaccination visit, diary cards will be provided to the subjects. Any 
unsolicited AEs (i.e. on the day of vaccination and during the next 29 days) 
occurring after vaccination will be recorded by all subjects. The subjects included in 
the safety and immune sub-cohort will also record body (axillary) temperature and 
any solicited local/general AEs (i.e. on the day of vaccination and during the next 6 
days). In case of illiterate subjects, a designated person (such as a family member or 
a field worker) may provide assistance to complete the diary cards. The subject will 
be instructed to return the completed diary card to the investigator at a later visit. In 
case a diary card is lost by the subject or he/she is unable to complete the diary card, 
the safety information should be captured retrospectively using a descriptive 
interview. This process will be documented in a site SOP by an Internal Operational 
Procedure (IOP). Please refer to the SPM for further details.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
154
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
155
Section 6.7
Biological sample handling and analysis
Please refer to the SPM and lab manual for details on biospecimen management 
(handling, storage and shipment).
(Amended 26 March 2013)
Section 6.7.1 Use of specified materials
When materials are provided by “The Collaboration”, it is MANDATORY that all 
clinical samples (including serum samples) be collected and stored exclusively using 
those materials in the appropriate manner. The use of other materials could result in the 
exclusion of the subject from the ATP analysis (See Section 11.5 for the definition of 
study cohorts/ data sets to be analysed). The investigator must ensure that his/her 
personnel and the laboratory(ies) under his/her supervision comply with this requirement. 
However, when “The Collaboration” does not provide material for collecting and storing 
clinical samples, appropriate materials from the investigator’s site must be used. Refer to 
the Module on Clinical Trial Supplies in the SPM and lab manual.
Section 6.7.2 Biological samples
Table 9
Biological samples
Sample type
Quantity
Unit
Time point
Subjects
Blood sampling for Safety 
assessment
At least 8
mL
Days 0, 7, 30 and 371
Safety and immune 
sub-cohort2
Blood sampling for 
Humoral responses
At least 2
mL
Days 0, 60 and Years 1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for CMI
At least 18 2.5
mL
Days 0, 60 and Years 1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for 
QuantiFERON® TB Gold
QFTG
At least 3
mL
Day 0 and Years 1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for 
QFTG
At least 3
mL
Day 0 and Year 3
All subjects3
Blood sampling for RNA 
expression profiling
At least 2.5
mL
Days 0 and Day 4434 and when 
TB diagnosis is confirmed
All subjects
Sputum sampling for TB 
diagnosis45
Approximately 5
mL
Throughout the study when 
pulmonary TB is suspected
All subjects with 
suspicion of 
pulmonary TB
Blood sampling for initial 
HIV testing - Step 1 
(Rapid test)
Finger prick or at 
least 2.5
mL
At screening
All subjects living in 
a region with HIV 
prevalence > 1%
When TB diagnosis is confirmed
All subjects 
diagnosed with TB
Blood sampling for HIV 
testing - Step 2 (Rapid 
test)
Finger prick or at 
least 2.5 
mL
At screening and when TB 
diagnosis is confirmed
All subjects positive 
at Step 156
Blood sampling for HIV 
testing - Step 3 (ELISA)
At least 2.5 
mL
At screening5
Discordant Rapid 
test results or if no 
Rapid test 
performed67
When TB diagnosis is confirmed
At least one positive 
Rapid test or if no 
Rapid test 
performed67
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
155
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
156
Sample type
Quantity
Unit
Time point
Subjects
Blood sampling for PCR -
Step 4
At least 2.5 
mL
When TB diagnosis is confirmed
Indeterminate ELISA 
results or no ELISA 
performed and at 
least one positive 
Rapid test67
Blood sampling for CD4 
count
At least 2.5
mL
When TB diagnosis is confirmed 
and confirmed HIV-positive
HIV positive 
subjects with TB 
diagnosis confirmed
1 Vitamin D levels will be measured at day 0 only.
2 Refer to Section 5.1 for sub-cohort description.
3 At study end (Year 3) QFTG testing will only be performed for subjects QFTG-negative at baseline.
34 The most informative time point for collection of blood samples for RNA expression profiling post dose 2 will be 
determined. The exact time point will be communicated to the investigators appropriately at the latest at study initiation. 
Additionally, samples for RNA expression profiling must be collected at the time of TB diagnosis. 
45 Three sputum samples, preferably taken in the morning, within a one week interval, will be collected whenever a 
subject presents with clinical suspicion of pulmonary TB.
56 HIV positive subjects at screening will be referred for confirmatory HIV diagnosis/management as per site SOPs.
67 Only the final conclusive diagnosis is to be recorded in the CRF.
Section 6.7.3
Laboratory assays
Table 11
Cell-Mediated Immunity (CMI)
System
Component
Challenge
Method
Unit
Cut-
off
Laboratory*
PBMCWhole 
blood
CD4+/CD8+ T cells 
expressing at least two 
immune markers (CD40L 
and/or IL-2 and/or TNF-
and/or IFN-)
M72
ICS -
intraCellular 
Cytokine 
Staining 
number of 
events per 
million cells 
N/A 
CEVAC**GSK 
Biologicals
*Refer to APPENDIX B for the laboratory addresses.
**Or as designate by GSK Biologicals
Table 12
RNA expression profiling
System
Component
Method
Unit
Laboratory*
Whole blood
RNA expression
Microarray
NA
COVANCE**
*Refer to APPENDIX B for the laboratory addresses.
**Or as designated by “The Collaboration”.
Table 13
Diagnostic test for pulmonary TB disease
System
Component
Method
Unit
Laboratory*
Component 
priority ranking
Sputum
Mycobacterium 
tuberculosis DNA
Xpert MTB/RIF 
assay
NA
As designated by 
“The Collaboration”
Central Laboratory
1
Sputum
Mycobacterium 
tuberculosis
Microbiological 
culture
NA
As designated by 
“The Collaboration”
Central Laboratory
2
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
156
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
157
Table 14
Diagnostic tests for HIV
System
Component
Method
Unit
Laboratory*
Whole Blood or Serum
Anti-HIV antibodies, 
screening step 1, step 2
HIV Rapid Test**
NA
As designated by “The
Collaboration” At the 
Investigator’s lab
Serum
Anti-HIV antibodies,
screening step 3
ELISA
NA
As designated by “The 
Collaboration” At the 
Central Laboratory
Whole Blood
HIV RNA,
screening step 4
HIV PCR
NA
As designated by “The 
Collaboration” At the 
Central Laboratory
Whole blood
CD4 cells
Flow cytometry
Cells/mm3
As designated by “The 
Collaboration” At the 
Central Laboratory
Table 15
Haematology, Serum Chemistry, Urine tests
System
Component
Method
Scale
Whole blood
Alanine amino transferase
As per laboratory 
standard procedures
Quantitative
Aspartate amino transferase
Creatinine
Bilirubin (total)
Platelets
Leucocytes
Erythrocytes
Haemoglobin
Vitamin D
IFN-release by T cells
QuantiFERON® TB 
Gold Assay
QualitativeQuantitative
Urine
-HCG
As per laboratory 
standard procedures
Qualitative
The laboratory that will perform Xpert MTB/RIF, Microbiological culture and HIV 
testing is not yet identified and will be defined before study start.
The laboratory that will perform RNA expression profiling is not yet identified and will 
be identified before study end.
Section
6.7.4.1
Diagnostic assays
For the safety and immune sub-cohort a QuantiFERON® TB Gold assay QFTG testing 
will be done prior to dose 1 at baseline (Day 0) for all subjects, at study end (Year 3) for 
all subjects QFTG-negative at baseline and yearly and post dose 2 (Years 1, 2 and 3) for 
subjects included in the safety and immune sub-cohort, to detect CMI responses to TB 
infection by measuring IFN-produced by memory T cells in whole blood after 
incubation with synthetic peptides of the Mtb-secreted antigens Early Secretory Antigen 
Target-6 (ESAT-6), and Culture Filtrate Protein-10 (CFP-10) and TB 7.7. These TB-
specific proteins stimulate a robust and detectable immune response in TB-infected and 
previously TB-infected people. In addition, QFTG testing will be done whenever a 
subject is diagnosed with TB disease.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
157
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
158
Section 6.7.4.2
Immunological read-outs
After collection, whole blood samples will be incubated with pool(s) of overlapping 
peptides covering the M72 antigen sequence and with the stimulation controls for 2 
hours in the presence of anti-CD28 and anti-CD49d antibodies. Subsequently, Fflow 
cytometry using a short-term stimulation Intracellular Cytokine Staining (ICS) assay on 
frozen Peripheral Blood Mononuclear Cells (PBMCs) will be used to characterise M72-
specific CD4+/CD8+ T cells expressing at least two immune markers (CD40L and/or IL-
2 and/or TNF-and/or IFN-) on Days 0, 60, and Years 1, 2 and 3. 
Complementary analyses may be performed. Flow cytometry using ICS on PBMCs may 
be used to evaluate M72-specific expression of other cytokines, including IL-13 and/or 
Il-17, and markers characterising memory and functionality responses as well as to 
characterise other TB antigen specific CD4+ and CD8+ T cells (such as PPD, Early 
Secretory Antigenic Target– 6 [ESAT-6], Culture Filtrate Protein-10 [CFP-10], etc).
Table 16
Immunological read-outs
Blood sampling time point
Sub-cohort 
Name
No. 
subjects
Component
Type of contact 
and time point
Sampling time 
point
Visit 2 (Day 0)
Pre Vacc
Safety and 
immune sub-
cohort
500450
M72-specific T-cells (ICS on whole blood PBMCs)
Anti M72 Ab (ELISA on serum)
Visit 7 (Day 60)
Post Vacc 2
M72-specific T-cells (ICS on whole blood PBMCs)
Anti M72 Ab (ELISA on serum)
Visit 8 (Year 1)
LTFU
M72-specific T-cells (ICS on whole blood PBMCs)
Anti M72 Ab (ELISA on serum)
Visit 9 (Year 2)
LTFU
M72-specific T-cells (ICS on whole blood PBMCs)
Anti M72 Ab (ELISA on serum)
Visit 10 ( Year 3)
LTFU
M72-specific T-cells (ICS on whole blood PBMCs)
Anti M72 Ab (ELISA on serum)
Section 6.7.4.3
Haematology/Biochemistry
Table 17
Biochemistry/haematology readouts
Blood sampling time point
Sub-cohort Name
No. 
subjects
Component
Type of contact and 
time point
Sampling 
time point
Visit 2 (Day 0)
Pre-Vacc
Safety and immune sub-
cohort
500 450
Hb, PLT, WBC
ALT
AST
Creatinine
Bilirubin (total)
Vitamin D
Visit 3 (Day 7)
Post-Vacc 1
Safety and immune sub-
cohort
500 450
Hb, PLT, WBC
ALT
AST
Creatinine
Bilirubin (total)
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
158
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
159
Blood sampling time point
Sub-cohort Name
No. 
subjects
Component
Type of contact and 
time point
Sampling 
time point
Visit 4 (Day 30)
Post-Vacc 1
Safety and immune sub-
cohort
500 450
Hb, PLT, WBC
ALT
AST
Creatinine
Bilirubin (total)
Visit 5 (Day 37)
Post Vacc 2
Safety and immune sub-
cohort
500 450
Hb, PLT, WBC
ALT
AST
Creatinine
Bilirubin (total)
Section 11.2
Secondary endpoints
Safety

Occurrence of grade 2 haematological and biochemical levels at:
Days 0, 7, 30 and 37
Immunogenicity

Evaluation of CMI responses with respect to components of the study vaccine, in the 
safety and immune sub-cohort:

Determined by the frequency of M72-specific CD4+/CD8+ T cells per million 
cells identified after in vitro stimulation, as expressing at least 2 immune markers 
among CD40L, IL-2, IFN-and TNF-.

Determined by the frequency of M72-specific CD4+/CD8+ T cells per million 
cells identified after in vitro stimulation, as expressing any combination of 
immune markers among CD40L, IL-2, IFN-and TNF-.
Time points: prior to dose 1 (Day 0) and post dose 2 (Day 60, Years 1, 2 and 3)
Section 11.3
Tertiary endpoints

Evaluation of CMI responses with respect to components of the study vaccine, in 
the safety and immune sub-cohort:

Determined by the frequency of M72-specific CD4+/CD8+ T cells per million 
cells identified after in vitro stimulation, as expressing any combination of 
immune markers among CD40L, IL-2, IFN-and TNF-.
Time points: prior to dose 1 (Day 0) and post dose 2 (Day 60 and Years 1, 2 and 3).

QFTG test result. 
Time points: prior to dose 1 (Day 0), post dose 2 (Year 3)
Section 11.4
Determination of sample size
The primary objective is to demonstrate that the lower limit of the 95% Confidence 
interval of vaccine efficacy (VE), obtained from the Cox proportional hazards 
regression model (VE=1-estimated hazard ratio) associated to the M72/AS01E vaccine 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
159
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
160
in preventing a first episodes of definite pulmonary TB disease meeting the first case 
definition is >0, is statistically significant at the 5 % two-sided significance level, to 
demonstrate that the M72/AS01E vaccine statistically reduces the number of definite TB
cases when compared to the control group (placebo).
Statistical analysis during the course of this study will include an interim analysis (IA) for 
advanced Phase III preparations and a final efficacy analysis futility, i.e. if a too low 
vaccine efficacy is observed at the time of the interim analysis, the trial will be stopped 
for futility. Therefore, no alpha adjustment is needed.
Null hypothesis (H0): Vaccine efficacy in prevention of definite pulmonary TB disease 
0% (interim and final analysis).
Alternative hypothesis (Ha): Vaccine efficacy in prevention of definite pulmonary TB 
disease > 0% (interim and final analysis).
Procedures to maintain the overall type I error for the primary objective to 0.05 (two-
sided):
The two sided Type I error alpha is divided as 0.001 and 0.049 at interim and final 
analysis, respectively. 
The study will only be fully analysed and unblinded early if extremely high efficacy is 
observed at the interim analysis. Therefore a very small alpha is used for the IA. 
Using a one-proportion test (Ha: p<0.5) logrank test with 80% power for a true VE of 
70% (hazard ratio of 0.3) and a two-sided 5% significance level, the number of cases 
required for a fixed sample design is 28 27 cases, based on the assumption that the 
hazard rates are proportional. These results are obtained by the program PASS 2005.
To obtain these 28 27 cases in total at final efficacy analysis, using assuming a mean 
yearly attack rate of 0.29 0.35 % in the control group, 3 years of follow-up for each 
subject and a rate of loss of follow-up time of 1312% due to drop out over the 3 years 
period, 7000 4500 subjects need to be enrolled based on the logrank test and parameters 
described above.
Sample size considerations for the safety and immune sub-cohort:
Approximately 450 subjects will be enrolled in the safety and immune sub-cohort (225 
subjects in each treatment group) with up to 150 subjects/contributing country (75 
subjects in each treatment group).
Assuming a standard deviation of log10(value*) of 0.40**, as observed in previous 
studies, a precision for the 95 % CI for log10(value*) of 0.052 or 0.092 will be obtained 
for a total samples size of 225 subjects vaccinated with M72/AS01E or 150 subjects
vaccinated with M72/AS01E/country respectively.
Precision of the log10(value*) is equal to half of the with of the 95% CI for 
log10(value*). The precision of the 95% CI and 95% CI can be derived by assuming 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
160
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
161
various levels of the value*. Precision of the 95% CI for GMT for a sample size of 150 
subjects and 450 subjects is presented in Table 26 and Table 27, respectively.
*GMT or median frequency of CD4 T cells expressing at least two immune markers 
among CD40L, IL-2, IFN-and TNF-
**A standard deviation around 0.40 for log10(GMT) and below 0.40 for log10(CD4 T 
cells expressing at least 2 immune markers) has been observed in previous studies.
Table 26
Precision for the 95% CI for GMT obtained from the 95% CI build on 
log10(GMT) assuming various levels of GMT for a sample size of 75 subjects
vaccinated with M72/AS01E
GMT
Log10(GMT)
precision for the 
95% CI for 
log10(GMT)
95% CI for the GMT
precision for the 
95% CI for the GMT
LL
UL
500
2.698970004
0.092
404.5479
617.9737
106.7129
1000
3
0.092
809.0959
1235.947
213.4258
2000
3.301029996
0.092
1618.192
2471.895
426.8515
3000
3.477121255
0.092
2427.288
3707.842
640.2773
4000
3.602059991
0.092
3236.384
4943.79
853.7031
5000
3.698970004
0.092
4045.479
6179.737
1067.129
6000
3.77815125
0.092
4854.575
7415.685
1280.555
CI: Confidence interval; GMT: Geometric Mean Titre; LL: Lower limit; UL: Upper limit
Table 27
Precision for the 95% CI for GMT obtained from the 95% CI build on 
log10(GMT) assuming various levels of GMT for a sample size of 225 subjects
vaccinated with M72/AS01E
GMT
Log10(GMT)
precision for the 
95% CI for 
log10(GMT)
95% CI for the GMT
precision for the 
95% CI for the GMT
LL
UL
500
2.698970004
0.052
443.578
563.5987
60.01036
1000
3
0.052
887.156
1127.197
120.0207
2000
3.301029996
0.052
1774.312
2254.395
240.0414
3000
3.477121255
0.052
2661.468
3381.592
360.0622
4000
3.602059991
0.052
3548.624
4508.79
480.0829
5000
3.698970004
0.052
4435.78
5635.987
600.1036
6000
3.77815125
0.052
5322.936
6763.185
720.1243
CI: Confidence interval; GMT: Geometric Mean Titre; LL: Lower limit; UL: Upper limit
Section 11.5.1
Total Vaccinated cohort
The Total Vaccinated cohort for efficacy will include all vaccinated subjects for whom 
data concerning efficacy endpoint measures are available and will include all TB cases 
occurring post dose 1.
Section 11.5.2
Modified Total vaccinated cohort for interim efficacy analysis
The modified TVC for interim efficacy analysis will include all subjects:
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
161
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
162

For whom two doses of study vaccines have been administered according to 
protocol (administration site and route)

Without randomisation failure

Without wrong replacment

Who did not present with TB disease, according to any case definition, during the 
vaccination period (day of first vaccination up to 1 month post dose 2).
Section 11.5.4
According-to-protocol cohort for analysis of immunogenicity
The ATP cohort for immunogenicity will include all subjects from the safety and immune 
sub-cohort that:

Received all two vaccinations according to protocol procedures within specified 
intervals.

Who complied with blood sampling schedules.

Who had biochemistry and haematology values within normal range before any 
vaccination (exclude only if all values were out of range).

For whom post vaccination blood samples are available.

Who did not receive a vaccine/medication that may lead to elimination of an ATP 
analysis.

Who did not present with a medical condition that may lead to elimination of an ATP
analysis.

For whom the randomization code has not been broken.

Who completed the whole vaccination course or if not, no blood samples should 
have been taken after discontinuation of the vaccination course.
Section 11.5.5
According-to-protocol cohort for analysis of QFTG status 
The ATP cohort for analysis of QFTG status  will include all subjects:

Who received two vaccinations according to protocol procedures within specified 
intervals.

For whom post vaccination QFTG blood samples are available.

Who did not receive a vaccine/medication that may lead to elimination of an ATP 
analysis.

Who did not present with a medical condition that may lead to elimination of an 
ATP analysis.

For whom the randomization code has not been broken.

With a negative QFTG test result at baseline.

With no indeterminate QFTG test result at any time point.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
162
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
163
Section 11.6
Derived and transformed data

The cut-off value for M72-specific antibody titres is 2.8 EU/mL.
Section 11.8
Analysis of efficacy
Vaccine efficacy will be estimated from a Cox proportional hazard regression model 
(VE=1-hazard ratio) and 95% CIs and Wald p-value will be derived. The primary 
analysis will be unadjusted but secondary analyses will evaluate the effect of potential 
covariates. As a primary analysis, vaccine efficacy will be estimated using a frequentist 
approach. In this analysis, vaccine efficacy is defined as 1-RR where RR is the Poisson 
rate ratio.
The rate in the vaccine group is equal to the number of cases in the vaccine group divided 
by the follow-up time. The rate in the control group is defined the same way. CIs and p-
values will be calculated using the exact method implemented in the Poisson procedure 
of the StatXact package provided by Cytel. This method is also available in proc genmod 
when using the exact option. 
At interim analysis, the success criterion for the primary objective is the following:
The lower limit of the 99.9% two-sided confidence interval for the VE against first 
occurrence of definite pulmonary TB disease, meeting the first case definition, is above 
0% (this corresponds to a two-sided alpha of 0.1%).
The interim analysis for advanced Phase III preparation will be performed after 
approximately half of the total number of definite pulmonary TB cases, meeting the first 
case definition, have accumulated in the ATP cohort for efficacy based on data that are as 
clean as possible.
At final efficacy analysis, the success criterion for the primary objective is the following:
The lower limit of the 95.1% two-sided confidence interval for the VE against first 
occurrence of definite pulmonary TB disease, meeting the first case definition is above 
0% (this corresponds to a two-sided alpha of 4.9%). 
As a secondary analysis, the rate ratio will be calculated taking into account country, 
gender and other co-variables as strata.
Kaplan-Meier survival curves for the vaccine and control groups will be presented 
together with p-values from the logrank test.
If the primary objective is met, the confirmatory secondary objective will be evaluated 
with the following success criterion:
The lower limit of the 95.1% two-sided confidence interval (CI) for the VE against first 
occurrence of Definite Xpert MTB/Rif positive pulmonary TB disease not associated with 
HIV-infection, meeting the second case definition, is above 0%.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
163
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
164
For all other secondary efficacy objectives, Kaplan-Meier survival curves will be 
plotted and compared by means of the logrank test. The magnitude of the vaccine 
efficacy will be estimated using Cox regression.
For the tertiary efficacy analysis, the analysis will be based on the ATP cohort for 
analysis of Mtb infection. The vaccine efficacy will be estimated as 1- the Rate Ratio 
(RR) where the rate is defined as the number of subjects QFTG- positive (converters) at 
study end divided by the number of subjects QFTG- negative at baseline, in each 
group. These two proportions will be compared using the Fisher exact test. 
Section 11.10

The number of subjects with grade 2 Clinical laboratory observations
abnormalities will be described tabulated.
Section 11.12.1
Sequence of analyses

An interim efficacy analysis for futility will be performed after approximately half of 
the total number of approximately 10 definiteXpert MTB/Rif positive pulmonary 
TB cases (approximately 40% of the target events) in confirmed HIV-negative 
subjects, meeting the first case definition, have accumulated in the ATP cohort
modified TVC for interim efficacy analysis, during the efficacy surveillance period 
starting 1 month post dose 2 (Day 60). If the study is stopped for futility, subjects 
will continue to be followed-up for safety up to 6 months post dose 2 and a study 
conclusion visit will be scheduled at the earliest convenient time point. All data 
(efficacy, safety and immunogenicity) collected up to last subject last visit (LSLV)
will be cleaned, unblinded and analysed.

Analysis of efficacy will be performed when 28 27 cases of definite pulmonary TB 
disease, meeting the first case definition, have accumulated in the ATP cohort for 
efficacy, during the efficacy surveillance period starting 1 month post dose 2 (Day 
60) or at the latest when all subjects have completed the Month 36 visit.
Section 11.12.2
Statistical considerations for interim analyses
To start advanced phase III preparations In order to avoid trial progression with a 
candidate vaccine with very low efficacy, an interim efficacy analysis for futility is 
planned, i.e. if a too low vaccine efficacy is observed at the time of the interim analysis, 
the trial will be stopped for futility. Therefore, no alpha adjustment is needed.
…
Stopping rules for futility will be defined in the statistical analysis plan for interim 
analysis.
Specifications for recommendations by the IDMC will be documented in the IDMC 
charter.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
164
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
165
APPENDIX A
Laboratory assays
Cell-mediated immune responses 
Stimulation of whole blood 
After collection, whole blood samples will be stimulated at 37°C with pool(s) of 
overlapping peptides covering the M72 antigen sequence and with the stimulation 
controls for 2 hours in the presence of anti-CD28 and anti-CD49d antibodies. Then, 
cytokine secretion inhibitor (Brefeldin A) will be added for an additional overnight 
incubation. The day after, red blood cells will be lysed and white blood cells will be 
washed and fixed prior to cryopreservation and kept in storage for subsequent 
cytometry analysis. 
Preparation of Peripheral Blood Mononuclear Cells
PBMCs will be isolated from whole blood cells by Ficoll hypaque gradient following 
GSK Bio standard procedures. After the washing steps, isolated PBMCs will be re-
suspended in 1 mL of 90% cold foetal calf serum and 10% DMSO to be frozen slowly to 
-70°C (+/-5C) or colder and transferred to liquid nitrogen for storage up to subsequent 
CMI analysis is described below.
Intracellular Cytokine Staining (ICS) using frozen PBMCs
Intracellular fluorescent staining for cytokines (ICS) provides information on the 
frequency of cells responding to one particular antigen; it allows to define the frequency 
of CD4+ and CD8+ T lymphocytes expressing molecules involved in immunity such as 
IFN-, IL-2, TNF-, and/or CD40L (conventional CD4+ and CD8+ T cell response 
markers). ICS will be performed on thawed PBMCs stimulated with pools of overlapping 
peptides covering the entire M72 sequence and/or other Mtb related antigens for 2 hours. 
Then an intracellular block (e.g. Brefeldin A) will be added to inhibit cytokine secretion 
for an additional overnight incubation. Thawed Ccells will subsequently be harvested, 
stained for surface markers (e.g. CD4+ or CD8+ for T cells) and then fixed. Fixed cells 
will then be made permeable and stained with labelled cytokine-specific antibody. Cells 
will then be washed, re-suspended in PBS and analysed by flow cytometry.
QuantiFERON® TB Gold assay Amended 21 March 2013)
For evaluation of Mtb complex infection, whether tuberculosis disease, latent TB 
infection or past TB infection,, the QuantiFERON®-TB Gold In-Tube Assay 
(Cellestis) will be used. QuantiFERON®-TB Gold In-Tube is an in vitro diagnostic test 
using peptide cocktails simulating ESAT-6, CFP-10 and TB7.7 proteins to stimulate 
cells in heparinised whole blood. These proteins are absent from all BCG strains and 
from most non-tuberculosis mycobacteria with the exception of M. kansarii, M. szulgai 
and M. marinum. The assay will be performed according to the manufacturer’s 
instructions. Briefly, blood is collected directly into QuantiFERON®-TB Gold
collection tubes including a Nil Control tube, TB antigen tube and Mitogen Control 
tube. The tubes should be  incubated for 16-24 hours at 37°C prior to harvesting 
plasma. IFN-concentrations in plasma are determined using the QuantiFERON®-
TB Gold ELISA kit.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
165
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
166
APPENDIX B
Clinical Laboratories
Table 29
Outsourced Laboratories
Laboratory
Address
CEVAC - University of Gent
De Pintelaan, 185 Gent
Belgium
COVANCE
401 Terry Avenue North
Suite 200
Seattle, Washington 98109
USA
Central laboratories
BARC South Africa Pty Ltd
Napier Road POB 8475
2000 Johannesburg
Republic of South Africa
KEMRI/CDCResearch Station, 
Kenya
Busia Road POB 1578-40100
Kisumu
Kenya
CIDRZ Zambia
Alick Nkhata Road
Kalingalinga Clinic Grounds
Lusaka
Zambia
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
166
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
167
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 5
eTrack study number and 
Abbreviated Title
115616 (TUBERCULOSIS-018)
Amendment number:
Amendment 5
Amendment date:
29 January 2014
Co-ordinating author:
, Scientific Writer, XPE 
Pharma&Science, contractor for GSK Biologicals
Rationale/background for changes:
Optimized study design and sample size by increasing event rate by focussing on 
IGRA positive subjects. Baseline screening for pulmonary TB as precautionary safety 
measures. Separate protocol for biobanking of blood samples for future research on 
biological correlates for TB disease.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Cover page
Contributing authors GSK 
Biologicals
!
, Clinical Research and 
Development LeadDirector Clinical 
Development
!
, Project Statistician
!
, Global Study 
ManagerStudy Delivery Manager
!
, Project Delivery Lead
!
, Project Manager Clinical 
Readouts
!
 Safety
ScientistPhysician
!
 Study Data 
Manager
!
, Senior Manager Clinical 
Regulatory Affairsand Labelling
!
, Global Regulatory Lead
Contributing Authors Aeras
!
, President & Chief 
ScientificExecutive Officer
!
, Director Clinical Development
Copyright 2012 - 20132014 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
167
29-JAN-2014
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
168
Sponsor Signatory Approval Page
Detailed Title 
A phase IIb, double-blind, randomised, placebo-
controlled study to evaluate the efficacy, safety and 
immunogenicity of GSK Biologicals’ candidate 
tuberculosis (TB) vaccine GSK 692342 against TB 
disease, in healthy adults aged 18-50 years, living in a 
TB endemic region.
Investigator Agreement Page
Detailed Title 
A phase IIb, double-blind, randomised, placebo-
controlled study to evaluate the efficacy, safety and 
immunogenicity of GSK Biologicals’ candidate 
tuberculosis (TB) vaccine GSK 692342 against TB 
disease, in healthy adults aged 18-50 years, living in a 
TB endemic region.
Synopsis
Rationale for the study and study design

Rationale for the study
In TB endemic settings the incidence of pulmonary TB disease is higher in people who 
have been infected with Mtb as evidenced by a positive Interferon gamma release assay 
(IGRA). For the present first phase II proof-of-concept trial focussing on this IGRA+ 
adult population maximizes the trial efficiency by increasing the event rate in the 
control group.
This Phase IIb study aims at collecting initial efficacy data and gathering further safety 
and immunogenicity data on the M72/AS01E vaccine candidate in healthy adults living in 
a TB endemic region. 

Rationale for the study design
This Phase IIb study is designed to evaluate the protective efficacy of the M72/AS01E
candidate TB vaccine against definite pulmonary TB disease not associated with HIV-
infection, versus placebo, following 2 injections given one month apart. The protective 
efficacy will be evaluated in baseline IGRA positive adults living in a TB endemic region 
aged 18-50 years, i.e. in an age range where the incidence of TB is high.
This study is an international, multicentre, phase IIb, double-blind, randomized, 
controlled trial. There will be follow-up for efficacy for approximatelyup to 3 years after 
vaccination via regular visits or contacts to screen for possible TB. 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
168
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
169
To minimize the potential confounding effect of HIV prevalenceinfection in the study 
population at baseline, HIV testing will be performed at screening in regions with a 
highand only HIV prevalence (> 1%).negative subjects will be enrolled.
An Independent Data Monitoring Committee (IDMC) will behas been constituted for this 
study to perform periodic safety reviews of the safety data and evaluate the interim 
efficacy analysis.
An IFN-positive T cell response induced by past or present Mtb infection, as measured 
by the QuantiFERON® TB Gold (QFTG) assay (Cellestis), will be evaluated at baseline 
for all subjects, at study end (Year 3) for all subjects QFTG-negative at baseline and 
yearly for subjects in the safety and immune sub-cohort. In addition, a QFTG assay will 
be performed whenever a subject is diagnosed with TB disease.
Objectives
Primary
The lower limit of the 9590% two-sided confidence interval (CI) for the VE (using a Cox 
regression model) against first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the first case definition, is above 0%.
Secondary
The lower limit of the 95 90% two-sided confidence interval (CI) for the VE (using a Cox 
regression model) against first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the firstsecond case definition, is above 0%.
Tertiary 
To evaluate the protective efficacy of two doses of the M72/AS01E candidate vaccine 
against Mtb infection, as measured by QFTG conversion.*

To identify candidate biological markers linked to the risk for TB disease. 
*QFTG conversion is defined as the change from a negative QFTG test result (value 
below the cut off for IFN-concentration) to a positive QFTG test result (value at or 
above the cut off for IFN-concentration) in two serial samples.
Synopsis Table 1
Study groups and epochs foreseen in the study 
Study groups
Number of subjects 
Age (Min/Max)
Epoch 001
M72AS01
22501753
18 - 50 years
x
Control
22501753
18 - 50 years
x
Sampling schedule:

Blood samples will be collected in the safety and immune sub-cohort for 
evaluation of biochemistry/haematology parameters (Days 0, 7, 30 and 37), CMI 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
169
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
170
responses (Days 0, 60 and Years 1, 2 and 3) and humoral immune responses 
(Days 0, 60 and Years 1, 2 and 3). Vitamin D levels will be measured at Day 0. 

Blood samples will be collected for QFTG testing at baseline (Day 0)screening
for all subjects, at study end (Year 3) for .

A respiratory sputum sample will be collected prior to vaccination in all 
subjects QFTG-negative at baseline and yearly for subjects included in the safety 
and immune sub-cohortfor nucleic acid amplification test to rule out pulmonary 
TB.

Blood samples for RNA expression profiling will be collected from all subjects 
(Days 0 and post dose 2) 

Blood samples will be collected for initial HIV testing at screening for all 
subjects. Repeat HIV testing will be performed at the last study visit V9, unless 
the subject has been confirmed HIV positive before V9.

Whenever a subject is diagnosed with TB disease, blood samples will be 
collected for HIV testing, mRNA expression profiling and QFTG testingHbA1c 
measurement. 
Data collection: Electronic Case Report Form (eCRF) - Inform™
Safety monitoring: an Independent Data Monitoring Committee (IDMC), operating 
under a charter, will behas been constituted for this study to oversee the study. They will 
perform safety reviews three times in the first year of enrolment and twice a year, or 
more frequently if deemed necessary on an ongoing basis for the duration of the study
and evaluate the interim efficacy analysis.
Case Definitions:
Fourth case definition – DefiniteMicrobiological pulmonary TB
Number of subjects: Approximately 4500.3506.
Endpoints: Secondary
Efficacy

Occurrence of grade 2 haematological and biochemical, in the safety and immune 
sub-cohort, levels at:
Days 0, 7, 30 and 37
Immunogenicity

Evaluation of CMI responses with respect to components of the study vaccine, in the 
safety and immune sub-cohort:

Determined by the frequency of M72-specific CD4+/CD8+ T-cells per million cells 
identified after in vitro stimulation, as expressing at least 2any combination of 
immune markers among CD40L, IL-2, IFN-and TNF-.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
170
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
171
Tertiary

Evaluation of CMI responses with respect to components of the study vaccine, in the 
safety and immune sub-cohort:

Determined by the frequency of M72-specific CD4+/CD8+ T cells per million 
cells identified after in vitro stimulation, as expressing any combination of 
immune markers among CD40L, IL-2, IFN-and TNF-.
Time points: prior to dose 1 (Day 0) and post dose 2 (Day 60 and Years 1, 2 and 3)

QFTG test result. 
Time points: prior to dose 1 (Day 0), post dose 2 (Year 3)

Description of RNA expression profile signatures in selected samples as a correlate 
of risk to describe protective and non-protective immune responses after 2 doses of 
M72/AS01E.
Time points: Prior to dose 1 (Day 0), post dose 2 and when TB is diagnosed.
LIST OF ABBREVIATIONS
IA
Interim Analysis
HbA1c
Glycated haemoglobin
IPT
Izoniazid Preventive Therapy
mRNA
messenger Ribonucleic Acid
RDE
Remote Data Entry
RNA
Ribonucleic acid
SOC
System Organ Class
GLOSSARY OF TERMS
QFTG conversion
The change from a negative QFTG test result (value below 
the cut off for IFN-concentration) to a positive QFTG test 
result (value at or above the cut off for IFN-
concentration) in two serial samples.
The QFTG assay detects memory T-cell responses against 
Mtb as a surrogate for exposure to/infection with Mtb. The 
QFTG does not directly measure the presence of Mtb. The 
QFTG does not indicate whether the immune response of a 
subject iswas able to eliminate the bacteria or whether Mtb 
is latently present
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
171
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
172
INTRODUCTION
TB is the second leading cause of mortality worldwide, leading to about 1.451.3 million 
deaths a year [WHO, 20112013]. It is estimated that a third of the world’s population is 
infected latently with the Mycobacterium tuberculosis (Mtb) bacilli. Although not more 
than 105-20% of infected individuals will become ill, the high number of infected people 
poses a great risk to individuals with reduced immunity who are at a higher risk for TB. 
The TB burden is compounded by the emergence of multi-drug resistant (MDR) and 
extensively-drug resistant (XDR) TB. Approximately 8.88.6 million incident cases of TB 
were reported in 20102012 globally. Most TB cases were in the South-East Asia region
(mainly India and China),) and Africa (58% and 27% respectively). Asia refers to the 
WHO Regions of South-East Asia and the Western Pacific regions (40%, 24% and 19% 
respectively). Of these incident cases, an estimated 1.1 million (13%) were Human 
Immunodeficiency Virus (HIV) positive [WHO, 20112013]. TB is the most common co-
existing condition in people who die from Acquired Immune Deficiency Syndrome 
(AIDS).
In subjects with concurrent Pulmonary TB disease receiving treatment the vaccination 
seemed to induced a higher incidence of grade 3 injection site reactions; this 
observation is under futher investigation. 
1.3. Rationale for the study and study design
1.3.1. Rationale for the study
The burden of Mtb disease, particularly when compounded by HIV-infection and the 
emergence of MDR and XDR strains, is significant in TB endemic countries/regions. In 
2010, approximately 40% of TB cases were reported in India and China, of which up to 
80% were pulmonary in nature [WHO,20112013]. 
In TB endemic settings the incidence of clinical TB disease is highest in people who 
have been infected with Mtb as evidenced by a positive Interferon gamma release assay 
(IGRA). For the present first phase II proof-of-concept trial focussing on this IGRA+
adult population maximizes the trial efficiency by increasing the event rate in the 
control group. 
This Phase IIb study aims at collecting initial efficacy data and gathering further safety 
and immunogenicity data on the M72/AS01E vaccine candidate in IGRA+healthy adults, 
or with stable chonic medical condition(s), living in a TB endemic region.
All study participants may be offered to consent to participate in a second and parallel 
study Sponsored by AERAS which aims to collect a supplemental set of pre- and post-
vaccination blood samples to constitute a Biobank. After completion of this study this 
Biobank will serve for investigations into biological correlates of risk for TB disease
and potentially correlates of protection. Please refer to this separate protocol for 
further information. 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
172
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
173
1.3.2. Rationale for the study design
The protective efficacy will be evaluated in IGRA+ adults living in a TB endemic region  
aged 18-50 years, i.e. in an age range where the incidence of tuberculosisTB is high 
(Figure 1).
The primary objective of this study is to evaluate the protective efficacy of two doses of 
the M72/AS01E candidate vaccine against definite pulmonary TB disease not associated 
with HIV-infection, as compared to placebo. To minimizeavoid the potential 
confounding effect of HIV prevalenceinfection in the study population at baseline, HIV 
testing will be performedrequired to be negative at screening in regions with a high HIV 
prevalence (>1%).
An Independent Data Monitoring Committee (IDMC) will behas been constituted for this 
study to perform periodic safety reviews of the safety data and evaluate the interim 
efficacy analysis.
A sub-cohort of subjects will be selected for specific follow-up for safety (solicited 
adverse events (AE) and selected Biochemistry and Complete Blood Count [CBC]) and 
immunogenicity. Unsolicited AEs and large swelling reactions, serious adverse events 
(SAEs), potential immune-mediated diseases (pIMDs), AEs leading to withdrawal and 
pregnancies will be recorded for all subjects. 
An IFN-positive T cell response induced by past or present Mtb infection, as measured 
by the QuantiFERON® TB Gold (QFTG) assay (Cellestis), will be evaluated at baseline 
for all subjects, at study end (Year 3) for all subjects QFTG-negative at baseline and 
yearly in safety and immune the sub-cohort. In addition, a QFTG assay will be performed 
whenever a subject is diagnosed with TB disease.
2. OBJECTIVES
2.1. Primary objective
The lower limit of the 9590% two-sided confidence interval (CI) for the VE (using a Cox 
regression model) against first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the first case definition, is above 0%
2.2. Secondary objective
Efficacy:
The lower limit of the 9590% two-sided confidence interval (CI) for the VE (using a Cox 
regression model) against first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the firstsecond case definition, is above 0%.
To evaluate the protective efficacy of two doses of the M72/AS01E candidate vaccine 
against DefiniteMicrobiological pulmonary TB disease meeting the fourth case 
definition, as compared to placebo.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
173
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
174
Immunogenicity:

Tertiary objective 

To evaluate the protective efficacy of two doses of the M72/AS01E candidate 
vaccine against Mtb infection, as measured by QFTG conversion.

To identify candidate biological markers linked to the risk for TB disease.
Refer to Section 11.3 for the definition of the tertiary endpoints.
Refer to the GLOSSARY OF TERMS for a definition of QFTG conversion.
3. STUDY DESIGN OVERVIEW
Figure 2 was updated to reflect the overview of the study design.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
174
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
175
Table 1 Study groups and epochs foreseen in the study 
Study Groups
Number of subjects 
Age (Min - Max) (age 
unit)
Epoch 001
M72AS01
22501753
18 - 50 years
x
Control
22501753
18 - 50 years
x

Sampling schedule;

Blood samples will be collected in the safety and immune sub-cohort for 
evaluation of biochemistry/haematology parameters (Days 0, 7, 30 and 37), CMI 
responses (Days 0, 60 and Years 1, 2 and 3) and humoral immune responses 
(Days 0, 60 and Years 1, 2 and 3). Vitamin D levels will be measured at Day 0.

Blood samples will be collected for QFTG testing at baseline (Day 0)screening
for all subjects, at study end (Year 3) for

A respiratory sputum sample will be collected prior to vaccination in all 
subjects QFTG-negative at baseline and yearly for subjects included in the safety 
and immune sub-cohortfor nucleic acid amplification test to rule out pulmonary 
TB.

Blood samples for RNA expression profiling will be collected from all subjects 
at predefined time points (Days 0 and Day 44*).

Blood samples will be collected for initial HIV testing at screening for all 
subjects. Repeat HIV testing will be performed at the last study visit V9, unless 
the subject has been confirmed HIV positive before V9.

Whenever a subject is diagnosed with TB disease, blood samples will be 
collected for HIV testing, mRNA expression profiling and QFTG testingHbA1c 
measurement. In addition, if a subject is HIV-positive, blood samples will be 
collected to determine CD4 cell counts.
*The most informative time point for collection of blood samples for RNA 
expression profiling post-dose 2 will be determined. The exact time point will be 
communicated to the investigators appropriately at the latest at study initiation.

Type of study: self-contained.

Data collection: electronic Case Report Form (eCRF). – Inform™).

Safety monitoring: an IDMC, operating under a charter, will behas been constituted 
for this study to oversee the study. They will perform safety reviews twice a year, or 
more frequently if deemed necessary and evaluate the interim efficacy analysis.

Diagnostic procedures for suspected Pulmonary TB: during the entire study (not 
for screening), when a subject presents with clinical suspicion of pulmonary TB, 
three respiratory sputum samples, preferably taken in the morning, within maximum 
a one week interval, must be collected for testing with Xpert MTB/RIF and 
microbiological culture. 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
175
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
176
5. STUDY COHORT
5.1. Number of subjects/centres
Approximately 45003506 men and women aged 18-50 years will be enrolled in the study. 
Enrolment will be terminated when target number of subjects is reached.
To ensure the gender of the study population is equally distributed between females and 
males, a cap has been put on the number of subjects per gender to be enrolled. A 
maximum of 60% of subjects from the same gender will be enrolled in the study and 
enrolment of females/males will be stopped at approximately 27002100 subjects of any 
gender maximum.
Table 4
Sub-cohorts
Sub-cohort name
Description of additional activities
Estimated number 
of subjects
Safety and immune 
sub-cohort
Safety parameters for this sub-cohort will be collected as follows:

Solicited AEs will be collected for 7 days (day of vaccination and 
6 subsequent days) following vaccination.

Serum biochemistry/haematology values will be measured at 
Days 0, 7, 30, and 37.
Approximately 450
Immunogenicity:

Humoral immunogenicity will be evaluated by measuring M72-
specific IgGs at Days 0 and 60 and Years 1, 2 and 3.

CMI will be evaluated by measuring M72-specific CD4+ and 
CD8+ T cells expressing at least 2 immune markers (CD40-L 
and/or IFN-γ and/or IL-2 and/or TNF-) at Days 0 and 60 and 
Years 1, 2 and 3.

The QuantiFERON status of subjects will be determined at 
Day 0 and Years 1, 2 and 3. and any combination among
CD40-L, IFN-g, IL-2 and TNF-a
5.2. Inclusion criteria for enrolment
All subjects must satisfy ALL the following criteria at study entry:

Baseline positive IGRA test result. 

Baseline negative HIV screen.

Baseline negative clinical screening questionnaire and negative sputum sample for 
Pulmonary TB disease. 

Female subjects of childbearing potential may be enrolled in the study, if the subject:

has practiced adequate contraception* for 3025 days prior to vaccination, and

has a negative pregnancy test on the day of screening and the day of first 
vaccination, and
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
176
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
177

has agreed to continue adequate contraception during the entire 
treatmentvaccination period and for 2 months after completion of the vaccination 
series.
5.3. Exclusion criteria for enrolment
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study:

Current TB disease or history of TB disease and/or treatment within the last 12 
months.for TB (including IPT). 

Documented HIV-positive subject*.
*HIV testing and pre-test counselling will be performed in areas with high 
prevalence of HIV (> 1%).

History of medically confirmed autoimmune disease (e.g. Type I diabetes, Lupus). 
6. CONDUCT OF THE STUDY
6.2.2.2. Treatment allocation to the subject
6.2.2.2.1. Study group and treatment number allocation
The target will be to enrol approximately 45003506 eligible subjects who will be 
randomly assigned to two study groups in a 1:1 ratio (approximately 22501753 subjects 
in each group). 
Allocation of the subject to a study group at the investigator site will be performed using 
aan internet based randomisation system on internet (SBIR). The randomisation 
algorithm will use a minimisation procedure accounting for:

Centre 

Gender: a maximum of 27002100 females/males will be recruited. 

TB disease categorised as history or no history of TB disease.
Minimisation factors will have equal weight in the minimisation algorithm.
The treatment numbers will be allocated by dose at the site of the investigator using 
SBIR.
After obtaining the signed and dated ICFinformed consent from the subject and having 
checked the eligibility of the subject, the site staff in charge of the vaccine administration 
will access SBIR. Upon providing the subject identification number, the randomisation 
system will determine the study group and will provide the treatment number to be used 
for the first dose. The number of each administered treatment must be recorded in the 
eCRFon the Vaccine Administration screen.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
177
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
178
6.4. General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical and operational information that 
does not impact the safety of the subjects.
6.4.1.1. Active follow-up for safety and efficacy
Subject safety follow-up and timely case capture of incident TB disease is of paramount 
importance. In addition to study visits at the study facilities, regular contacts (every two 
months) with the study subjects must be maintained using one or more of the following 
methods:

Regular interval home visits by site staff.

Phone calls to inquire about current health status, completed by home visits if the 
subject cannot be reached.

21-way short message service (SMS)sms) reminders and/or 2-way sms exchange. 
6.4.3. Diagnostic procedures for the detection of suspected pulmonary TB 

Additionally if TB is confirmed a serological test (and pre-test counselling) for HIV-
infection must be performed to rule out HIV co-infection and a blood sample for 
RNA expression profiling and QFTG testing must be taken. If the subject is HIV-
positive, additional testing must be performed to measure CD4 cell counts. Diabetes 
will be screened for by a Hb Ac1 test. 

Results of HIV testing, including CD4 cell counts if applicable, and QFTG testing 
must be recorded in the subjects’ eCRF.
6.4.3. Procedures for fatalities
Verbal Autopsy reports that are shared with GSK Biologicals shouldthe collaboration or 
any vendors acting on behalf of the collaboration must be anonymised, i.e. all 
personally identifiable information should be removed. In the event that this occurs a 
GSK data privacy breach form will need to be completed.
6.4.5.2. Independent Data Monitoring Committee
In order to ensure the safety of the subjects during the entire study period, an Independent 
Data Monitoring Committee (IDMC) will behas been appointed to monitor the safety and 
tolerability of the vaccine/placebo administered in the trial and, if necessary, make 
recommendations to the sponsor concerning the modification or termination of the trial. 
The IDMC will perform safety reviews three times in the first year and twice a year or 
more frequently if deemed necessary on an ongoing basis during the study period. 
The IDMC will consistconsists of clinical experts who are not involved in the conduct of 
the study and an independent statistician. 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
178
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
179
If during the course of enrolment and vaccination two or more related grade 2 or 3 
respiratory AE are observed an ad hoc IDMC will be convened. 
6.4.5.3. Planned safety review 
A planned safety review after the first 100 subjects have been enrolled and vaccinated 
will be performed. The SRT will review blinded safety summaries and the IDMC will 
review unblinded safety summaries.
6.4.5.4. Rules for vaccination 
At individual subject level

No second dose should be administered in a given subject who experiences Grade 
3 redness and swelling, i.e. 100mm, post dose 1 or  Grade 2 or 3 respiratory AE 
post dose 1. 

No second dose should be administered in a given subject who develops TB disease 
after dose 1. 
At study level

An ad hoc IDMC review will be called if 2 or more subjects experience related 
Grade 2 or higher respiratory AEs within 90 days after any dose.

Further enrolment and vaccination will be suspended if within 90 days after any 
study vaccine dose any of the following events are observed:

Related respiratory AE with Fatal outcome

Two or more subjects experiencing Grade 3 related Respiratory AE 

An ad hoc IDMC meeting will be called urgently for review. Vaccination may only 
be allowed to resume pending final VSMB approval. 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
179
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
180
Table 6 was inserted and the table number has been updated. Table 7 was 
updated with the new outline of study procedures.
Table 6 Safety holding rules for vaccination 
Event
Grade
Occurrences
Action for subject(s)
Trial actions
Redness/Swelling 
at injection site
(within 30 days after dose 1)
Grade 3
(>100mm)
any 
subject(s)
No dose 2 in same 
subject(s), 
keep in efficacy follow-
up
-
TB disease (after dose 1)
n/a
Any 
subject(s)
No dose 2 in same 
subject(s) , 
keep in efficacy follow-
up
-
Respiratory SOC AE
(within 90 days after dose 1)
Grade ≥2
1 subject
No dose 2 in same 
subject(s),
but keep in efficacy 
follow-up
Clinical assessment & 
further investigation at 
investigator discretion
-
Respiratory SOC AE
(within 90 days after dose 1)
Grade ≥2 
related
≥2 subjects
Ad hoc
IDMC review
Respiratory SOC SAE
Related & 
Fatal
≥1 subject
-
Study Hold,
IMDC Review,
VSMB
Respiratory SOC AE
(within 90 days after dose 1)
Grade ≥3, 
related
≥2 subjects
No dose 2 in same 
subject(s)
Clinical assessment & 
further investigation at 
investigator discretion
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
180
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
181
Table 7 List of study procedures 
Visit 1 Screening 
visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 6
Contact 1,  
2, 3 and 4
Visit 7
Contact 5, 
6, 7, 8, 9
Visit 8
Contact 10, 
11, 12, 13, 14
Visit 9
Time point(s)
D-30 to D0
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2 Post V2 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
All subjects 
Informed consent
●
Check inclusion/exclusion 
criteria
●
●
Collect demographic data
●
Medical history
●
●
Physical examination
●
History-directed physical 
examination
O
O
O
O
O
O
Resting vital signs
O
O
HIV testing2 (up to 2.5 
mL/test) 
●
●
Record weight3
●
●
●
●
Documentation of history 
of BCG 
vaccination/presence of 
scar
●
Documentation of history 
of TB household contacts
●
Pregnancy test (-HCG 
urine)
●
●
●
Study group and treatment 
number allocation for first 
dose
O
Treatment number 
allocation for second dose
O
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
181
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
182
Visit 1 Screening 
visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 6
Contact 1,  
2, 3 and 4
Visit 7
Contact 5, 
6, 7, 8, 9
Visit 8
Contact 10, 
11, 12, 13, 14
Visit 9
Time point(s)
D-30 to D0
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2 Post V2 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Vaccination 
●
●
Recording of administered 
treatment number
●
●
Check contraindications to 
subsequent vaccination
●
●
Recording concomitant 
medication/vaccination
●
●
●
●
●
●
●
●
●
●
●
●
Recording intercurrent 
medical condition
●
●
●
●
●
●
●
●
●
●
●
●
Distribution of diary cards
O
O
Return of diary cards
O
O
Recording of unsolicited 
AEs and large swelling 
reactions
●
●
●
●
●
●
Pre-vaccination 
assessment (including 
temperature)
●
●
Blood sampling for RNA 
expression profiling (2.5 
mL)5
●
●
Blood sampling for QFTG 
(3 mL)
●
Sputum collection for 
Xpert testing
●
Reporting SAEs
●4
●
●
●
●
●
●
●5
●4
●4
●4
●4
●4
Reporting pIMDs
●
●
●
●
●
●
●6
Reporting pregnancy
●
●
●
●
●
●
●86
Diagnostic procedures for 
suspected pulmonary TB7
●
●
●
●
●
●
●
●
●
●
●
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
182
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
183
Visit 1 Screening 
visit
Visit 2 Visit 31
Visit 4
Visit 51
Visit 62
Visit 6
Contact 1,  
2, 3 and 4
Visit 7
Contact 5, 
6, 7, 8, 9
Visit 8
Contact 10, 
11, 12, 13, 14
Visit 9
Time point(s)
D-30 to D0
D 0
D 7
D 30
D 37
D 44
M 2
M 4, 6, 8, 
10
M 12
M 14, 16, 
18, 20, 22
M 24
M 26, 28, 30, 
32, 34
M 36
Sampling Time point(s)
Pre V
Pre V Post V1 Post V1 Post V2 Post V2 Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Post V2
Dose
1
2
Documentation of TB 
cases8
●
●
●
●
●
●
●
●
●
●
●
Safety and immune sub-
cohort
Measuring Vitamin D
●
Recording of solicited AEs
●
●
●
●
CBC (Hb, PLT and WBC), 
ALT, AST, creatinine, 
bilirubin (8 mL)
●
●
●
●
Blood sampling for Wh.Bl.
CMI (2.5 mL)
●
●
●
●
●
Blood sampling for 
humoral immunogenicity (
2 mL)
●
●
●
●
●
Study conclusions for all 
subjects
●
Note: The double border at Month 36 indicates the final analyses which will be performed on all data obtained up to month 36. 
Pre V: Pre Vaccination; V: Vaccination; Post V: Post Vaccination
● is used to indicate a study procedure that requires documentation in the individual eCRF.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
1 Only subjects in the safety and immune sub-cohort need to come for this visit.
2 The most informative time point for collection of blood samples for RNA expression profiling post dose 2 will be determined. The exact time point will be communicated to the 
investigators appropriately at the latest at study initiationHIV testing, pre-test at screening in areas wereand post-test counselling will be performed whenever a HIV prevalence > 
1%test is done, according to the procedures detailed inTable 10.
3 Weight also needs to be recorded whenever there is suspicion of TB disease.
4 Only SAEs related to study participation or concurrent GSK medication/vaccine.
5 Samples for RNA expression profiling will also be taken at the time of TB diagnosis SAEs not related to study participation or concurrent GSK medication/vaccines will be recorded 
until 6 months post dose 2 (M7). 
6 Samples for QFTG testing will also be taken at the time of TB diagnosis To be recorded until 6 months post dose 2 (M7). 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
183
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
184
7 Only for subjects QFTG-negative at baseline Sputum samples for Xpert MTB/RIF testing and microbiological culture will be taken throughout the study if a subject presents with 
clinical suspicion of pulmonary TB disease. Three sputum samples, preferably taken in the morning and within max. one week, must be collected. Additionally, when a subject is 
diagnosed with TB, screening for diabetes (HbA1C) and HIV testing must be performed according to the procedures detailed inTable 10. Up to 2.5mL of blood will be collected per 
test. If the subject is confirmed HIV-positive, blood samples must be taken (2.5 mL) to measure CD4 counts. 
8 Documentation of TB cases will be done throughout the study, starting at Visit 3 (Day 7); this includes documentation of cases during active and passive follow-up and monitoring of 
medical facilities and pharmacies. 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
184
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
185
Table78
Intervals between study visits for all subjects 
Interval
Allowed interval1
Visit 1 - Visit 2
0 days - 30 days
Visit 2 - Visit 4
26 days - 35 days
Visit 4 - Visit 6
1 days - 25 days 2
Visit 4 - Visit 76
14 26 days -  - 35  days
Visit 4 - Visit 87
10 months - 12 months
Visit 4 - Visit 98
22 months -24 months
Visit 4 - Visit 109
34 months - 36 months
Visit n – next contact
6 weeks – 12 weeks
Contact n – contact n+1
6 weeks – 12 weeks
1 Subjects may not be eligible for inclusion in the ATP cohort for analysis of immunogenicity and efficacy if they make 
theattend for a study visit outside this interval.
2 The most informative time point for collection of blood samples for RNA expression profiling post dose 2 will be 
determined. The exact time point will be communicated to the investigators appropriately at the latest at study initiation.
6.6.5. Medical history
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF. In particular, history of TB 
disease* and/or previous treatment for tuberculosis, chronic pulmonary conditions (such 
as COPD, silicosis), history of smoking and diabetes* must be recorded (* type I diabetes
is an exclusion criterion).
6.6.7. History directed physical examination 
Perform a history directed physical examination. If the investigator determines that the 
subject’s health on the day of vaccination temporarily precludes vaccination, the visit will 
be rescheduled within the window period (Table 9).
6.6.10. Assess pre-vaccination body temperature
The axillary, rectal, oral or tympanic body temperature of all subjects needs to be 
measured prior to any study vaccine administration. The preferred route for recording 
temperature in this study will be axillary. If the subject has fever [fever is defined as 
temperature 37.5°C/99.5°F for oral, axillary or tympanic route, or 38.0°C/100.4°F for 
rectal route] on the day of vaccination, the vaccination visit will be rescheduled within 
the allowed interval for this visit (see Table 9).
6.6.12.1. Blood sampling for safetyand immune response assessments and QFTG 
status

For all subjects: 

A volume of at least 3 mL of whole blood shouldmust be drawn for QFTG 
testing at each predefined time point (screening (Table 11)

For all subjects:
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
185
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
186

A volume of at least 2.5 mL of whole blood will be collected directly in a 
Paxgene™ Blood RNA Tube providing pure RNA for accurate detection and 
quantification of RNA expression profiles (“transcriptomics”) at each predefined 
time point* (Table 9).

At screening, HIV testing must be performed according to the procedures 
detailed in Table 9 in regions with high HIV prevalence (> 1%). Up to 
approximately 2.5 mL of blood will be collected for each test. 

A volume of at least 3 mL of whole blood should be drawn for QFTG testing at 
each predefined time point** (Table 9)
*Blood sampling for RNA expression profiling is planned for Day 0 (Visit 2) and 
Visit 6 (post dose 2). The most informative time point for collecting whole blood 
samples for RNA expression profiling post dose 2 will be determined. The exact 
time point will be communicated to the Investigators appropriately at the latest at 
study initiation.
**At study end (Year 3) QFTG testing will only be performed for all subjects 
QFTG-negative at baseline.

Whenever a subject is diagnosed with TB disease:

Screening for diabetes and HIV testing must be performed according to the 
procedures detailed in Table 10. Up to approximately 2.5 mL of blood will be 
collected for each test. Additionally, if HIV is confirmed, at least 2.5 mL of 
blood will be collected to measure CD4 counts.

A volume of at least 2.5 mL of whole blood will be collected directly in a 
Paxgene™Blood RNA Tube providing pure RNA for accurate detection and 
quantification of RNA expression profiles (“transcriptomics”).

A volume of at least 3 mL of whole blood should be drawn for QFTG testing.
6.6.12.2. Sputum sample collection for TB screening 
A single sputum sample must be collected from all subjects going through screening 
for testing using Xpert. 
6.6.12.3. Sputum sample collection for TB diagnosis 
All subjects Subjects suspected with Pulmonary TB will be required to provide 3 sputum 
samples, preferably taken in the morning, within maximum a one week interval, of 
approximatelypreferably up to 5 mL to test for Mtb using the Xpert MTB/RIF assay and 
microbiological culture whenever the subject presents with clinical suspicion of 
pulmonary TB. If needed, induction of sputum through nebulisation of hypertonic saline 
may be performed. 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
186
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
187
6.6.15. Check and record concomitant medication/vaccination and intercurrent 
medical conditions

The site staff or Investigator should not write on the diary card, this information 
should be captured in the source notes. This process will be documented in a site 
SOP. Please refer to the SPM for further details.

Verify completed diary cards during discussion with the subject on Visits 2, 3*, 4, 5* 
and 7. 6.

Collect diary cards from the subjects at Visits 4 and 7. 6.

Any unreturned diary cards will be sought from the subject through telephone call(s) 
or any other convenient procedure. The investigator will transcribe the collected 
information into the eCRF in English.Inform™ in English. *Only for subjects 
included in the safety and immune sub-cohort.
6.6.16. Study conclusion
The investigator will:

review data collected to ensure accuracy and completeness.
complete the Study Conclusion screen in the eCRF.Inform™.
6.7. Biological sample handling and analysis
Under the following circumstances, additional testing on the samples may be performed 
by GSK Biologicals, by laboratories working for GSK Biologicals, by laboratories 
working in collaboration with GSK and by laboratories involved in studies ancillary to 
TB-018, outside the scope of this protocol.
6.7.2.1. Protocol mandated testing and enpoints 
Table 910
Biological samples 
Sample type
Quantity
Unit
Time point
Subjects
Blood sampling for Safety 
assessment
At least 8
mL
Days 0, 7, 30 and 371
Safety and immune 
sub-cohort2
Blood sampling for 
Humoral responses
At least 2
mL
Days 0, 60 and Years 1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for CMI
At least 2.5
mL
Days 0, 60 and Years 1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for QFTG
At least 3
mL
Day 0 and Years 1, 2, 3
Safety and immune 
sub-cohort2
Blood sampling for QFTG
At least 3
mL
Day 0 and Year 3At screening
All subjects3
BloodSputum sampling 
for RNA expression 
profilingTB screening
At least 2.Up to 5
mL
Days 0 and Day 444 and when 
TB diagnosis is confirmedAt 
Screening
All subjects
Sputum sampling for TB 
diagnosis53
Approximately 5
mL
Throughout the study when 
pulmonary TB is suspected
All subjects with 
suspicion of 
pulmonary TB
Blood sampling for initial 
Finger prick or at 
mL
At screening, 
All subjects living in 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
187
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
188
Sample type
Quantity
Unit
Time point
Subjects
HIV testing - Step 1 
(Rapid test)
least 2.5
At Visit 9 (study end)
a region with HIV 
prevalence > 1%
When TB diagnosis is confirmed
All subjects 
diagnosed with TB
Blood sampling for HIV 
testing - Step 2 (Rapid 
test)
Finger prick or at 
least 2.5 
mL
At screening and when TB 
diagnosis is confirmed
All subjects positive 
at Step 16
Blood sampling for HIV 
testing - Step 3 (ELISA)
At least 2.5
mL
At screening5, 
At Visit 9 (study end)
Discordant Rapid 
test results or if no 
Rapid test 
performed75
At least one positive 
Rapid test7
When TB diagnosis is confirmed
Blood sampling for PCR -
Step 4
At least 2.5
mL
When TB diagnosis is confirmed
Indeterminate ELISA 
results75
Blood sampling for CD4 
count
At least 2.5
mL
When TB diagnosis is confirmed 
and confirmed HIV-positive
HIV positive 
subjects with TB 
diagnosis confirmed
Blood sampling for 
HbA1C
At least 2.5
mL
When TB diagnosis is 
confirmed
Subjects with TB 
diagnosis 
confirmed
1 Vitamin D levels will be measured at day 0 only.
2 Refer to Section 5.1 for sub-cohort description. 
3 At study end (Year 3) QFTG testing will only be performed for subjects QFTG-negative at baseline.
4 The most informative time point for collection of blood samples for RNA expression profiling post dose 2 will be 
determined. The exact time point will be communicated to the investigators appropriately at the latest at study initiation. 
Additionally, samples for RNA expression profiling must be collected at the time of TB diagnosis. 
53 Three sputum samples, preferably taken in the morning, within a one week interval, will be collected whenever a 
subject presents with clinical suspicion of pulmonary TB.
64 HIV positive subjects at screening will be referred for confirmatory HIV diagnosis/management as per site SOPs.
75 Only the final conclusive diagnosis is to be recorded in the CRF.
Table1112
Cell-Mediated Immunity (CMI) 
System
Component
Challenge
Method
Unit
Cut-off
Laboratory*
Whole 
blood
CD4+/CD8+ T cells expressing at 
least two immune markers 
(CD40L and/or IL-2 and/or TNF-
and/or IFN-) and any 
combination among CD40-L, 
IFN-g, IL-2 and TNF-a
M72
ICS -
intraCellular 
Cytokine 
Staining 
number of 
events per 
million cells 
N/A 
GSK 
Biologicalsor 
as 
designated 
by GSK
*Refer to APPENDIX B for the laboratory addresses.
Table 12 has been deleted:
Table 12
RNA expression profiling (Amended 26 March 2013)
System
Component
Method
Unit
Laboratory*
Whole blood
RNA expression
Microarray
NA
COVANCE**
*Refer to APPENDIX B for the laboratory addresses.
**Or as designated by “The Collaboration”.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
188
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
189
Table13
Diagnostic tests for pulmonary TB disease 
System
Component
Method
Unit
Laboratory*
Component 
priority ranking
Sputum
Mycobacterium 
tuberculosis DNA
Xpert MTB/RIF 
assay
NA
Central Laboratory
1
Sputum
Mycobacterium 
tuberculosis
Microbiological 
culture
NA
Central Laboratory
2
Sputum
Mtb
Strain Typing
NA
Central lab
3
*Refer to APPENDIX B for the laboratory addresses.
Table 14
Diagnostic tests for HIV 
System
Component
Method
Unit
Laboratory*
Whole Blood or Serum
Anti-HIV antibodies, 
screening step 1, step 2
HIV Rapid Test**
NA
At the Investigator’s 
lab
Serum
Anti-HIV antibodies,
screening step 3
ELISA
NA
At the Central 
Laboratory
Whole Blood
HIV RNA,
screening step 4
HIV PCR
NA
At the Central 
Laboratory
Whole blood
CD4 cells
Flow cytometry
Cells/mm3
At the Central 
Laboratory
*Refer to APPENDIX B for the laboratory addresses.
**Two different Rapid HIV tests to be used sequentially
6.7.4. Biological samples evaluation per protocol 
6.7.4.1. Diagnostic assays 
Xpert MTB/RIF testing (Cepheid) and microbiological culture will be performed on three 
sputum samples, preferably taken in the morning, within a maximum one week interval, 
for all subjects presenting with clinical suspicion of pulmonary TB throughout the entire 
study.
HIV testing and pre-test and post-test counselling will be performed at screening in 
regions with high HIV prevalence (> 1%). HIV positive subjects at screening will be 
referred for confirmatory HIV diagnosis/management as per site SOPs and won’t be 
enrolled (exclusion criterion).
Whenever a subject is diagnosed with TB disease, an HIV test (and pre-test counselling) 
must be performed to rule out HIV co-infection. HbA1c measurement will also be 
performed. If a subject is diagnosed with HIV, additional tests to measure CD4 cell 
counts will be performed. Subjects with a positive test result will be referred for HIV 
treatment.
QFTG testing will be done at baseline (Day 0) for all subjects, at study end (Year 3) for 
all subjects QFTG-negative at baseline and yearly (Years 1, 2 and 3) for subjects 
included in the safety and immune sub-cohort, to detect CMI responses to TB infection 
by measuring IFN-produced by memory T cells in whole blood after incubation with 
synthetic peptides of the Mtb-secreted antigens Early Secretory Antigen Target-6 (ESAT-
6), Culture Filtrate Protein-10 (CFP-10) and TB 7.7. These TB-specific proteins stimulate 
a robust and detectable immune response in TB-infected and previously TB-infected 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
189
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
190
people. In addition, QFTG testing will be done whenever a subject is diagnosed with TB 
disease.
All diagnostic assays will be carried out at the designated central laboratory of the 
investigator or in a laboratoryas designated by “The Collaboration”. 
6.7.4.2. Immunological read-outs 
Blood will be collected at specific time points to assay for immunological readouts.Table 
16 details the main immunological read-outs.
After collection, whole blood samples will be incubated with pool(s) of overlapping 
peptides covering the M72 antigen sequence and with the stimulation controls for 2 hours 
in the presence of anti-CD28 and anti-CD49d antibodies. Subsequently, flow cytometry 
using a short-term stimulation Intracellular Cytokine Staining (ICS) assay will be used to 
characterise M72-specific CD4+/CD8+ T cells expressing at least two immune markers 
or any combination of markers, i.e. single, double, triple, quadruple, (CD40L and/or 
IL-2 and/or TNF-and/or IFN-) on Days 0, 60, and Years 1, 2 and 3.
The humoral immune response will be evaluated by assessment of antibody titres to M72 
by specific ELISA on Days 0 and 60, and Years 1, 2 and 3. 
Table 16
Immunological read-outs 
Blood sampling time point
Sub-cohort 
Name
No. 
subjects
Component
Type of contact 
and time point
Sampling time 
point
Visit 2 (Day 0)
Pre Vacc
Safety and 
immune sub-
cohort
450
M72-specific T-cells (ICS on whole blood)
Anti M72 Ab (ELISA on serum)
Visit 76 (Day 60)
Post Vacc 2
M72-specific T-cells (ICS on whole blood)
Anti M72 Ab (ELISA on serum)
Visit 87 (Year 1)
LTFU
M72-specific T-cells (ICS on whole blood)
Anti M72 Ab (ELISA on serum)
Visit 98 (Year 2)
LTFU
M72-specific T-cells (ICS on whole blood)
Anti M72 Ab (ELISA on serum)
Visit 109 ( Year 
3)
LTFU
M72-specific T-cells (ICS on whole blood)
Anti M72 Ab (ELISA on serum)
Vacc: Vaccination
LTFU: Long Term Follow-up
Microarray analysis will be performed on whole blood samples collected in PAXgene® 
Blood RNA tubes (PreAnalytiX®). The total purified RNA extract will be converted to 
cDNA by Reverse Transcriptase PCR and hybridised to a microarray chip that contains 
probe sets covering a substantial portion of the human transcriptome (which is the 
collective set of expressed mRNA). Microarray data will be analysed using 
bioinformatics approaches. Further analysis of mRNA expression profiles and validation 
might be performed by quantitative Reverse Transcriptase - Polymerase Chain Reaction 
or any updated technique, such as deep sequencing.
RNA expression profiling will be performed on a selected number of subjects’ samples to 
compare cases and non-cases within the control group, within the M72AS01 group and 
between groups.
The expected outcome of this analysis is to arrive at a RNA expression profile signature 
as a correlate of risk that could describe non-protective immune responses.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
190
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
191
7.5. Contraindications to subsequent vaccination

Grade 3 local symptoms redness and swelling, i.e. >100mm or Grade ≥2 
respiratory AE following the administration of vaccine(s).
Fever is defined as temperature ≥ 37.5°C/99.5°F on oral, axillary or tympanic setting, or 
≥ 38.0°C/100.4°F on rectal setting. The preferred route for recording temperature in this 
study will be axillary
9.1. Safety definitions
Examples of an AE include:
If subjects observe any large injection site reaction, they should contact the study 
personnel and visit the investigator’s office for evaluation as soon as possible.
A large injection site reaction is:

a swelling that measures more than 100 mm across where the vaccine was given, 
or

a noticeable irregular/uneven swelling where the vaccine was given, or

a noticeable increase in size of the arm that interferes with or prevents everyday 
activities (e.g., writing, use of computer, school attendance, sleeping, etc.). 
In case of questions or uncertainties, the subject/subject’s parent(s)/guardian(s) should 
contact the investigator by phone and the investigator will determine whether or not a 
visit should be arranged.
The investigator will record detailed information describing the AE on a specific large 
injection site reaction screen in the eCRF. An SAE report should also be completed if 
the large injection site reaction meets the definition of SAE.
Table 20 Solicited adverse events 
Solicited local (injection site) AEs
Solicited general AEs
Pain at injection site
Fatigue
Redness at injection site*
Fever
Swelling at injection site
GastrointestinalRespiratory Symptoms†
Headache
Malaise
Myalgia
*In case the principal investigator or designate is unable to determine the extent of redness on darkly pigmented skin, it 
will be reported as non-interpretable in the eCRF and Diary Card.
†GastrointestinalRespiratory symptoms include nausea, vomiting, diarrhoea and/cough, blood in sputum, purulent 
sputum, shortness of breath or abdominaldifficulties breathing, chestwall pain
Table 21 Toxicity grading table for laboratory abnormalities footnotes updated:
(source:FDA, 2007).
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
191
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
192
Table 24 Intensity scales for solicited symptoms in adults
Adults
Adverse Event
Intensity grade
Parameter
Pain at injection site
0
None
1
Mild: Any pain neither interfering with nor preventing 
normal every day activities.
2
Moderate: Painful when limb is moved and interferes with 
every day activities.
3
Severe: Significant pain at rest. Prevents normal every 
day activities.
Redness at injection site
Record greatest surface diameter in mm
Swelling at injection site
Record greatest surface diameter in mm
Fever*
Record temperature in °C/°F
Headache
0
Normal
1
Mild: Headache that is easily tolerated
2
Moderate: Headache that interferes with normal activity
3
Severe: Headache that prevents normal activity
Fatigue
0
Normal
1
Mild: Fatigue that is easily tolerated
2
Moderate: Fatigue that interferes with normal activity
3
Severe: Fatigue that prevents normal activity
Gastrointestinal 
symptomsRespiratory symptoms 
(cough, blood in sputum, 
purulent sputum, shortness of 
breath or difficulties breathing, 
chestwall pain)
0
GastrointestinalNo symptoms normal
1
Mild: Gastrointestinal symptoms that are easily tolerated
2
Moderate: Gastrointestinal symptoms that interfere with 
normal activity
3
Severe: Gastrointestinal symptoms that prevent normal 
activity
Malaise
0
Normal
1
Malaise that is easily tolerated
2
Malaise that interferes with normal activity
3
Malaise that prevents normal activity
Myalgia
0
Normal
1
Myalgia that is easily tolerated
2
Myalgia that interferes with normal activity
3
Myalgia that prevents normal activity
10.4. Screen and baseline failures
If the investigator believes there is a reasonable reason to do so, screening procedures 
(including, but not limited to, the QTF screening in the case of an intermediate result) 
may only be repeated once, either individually or in their entirety.
11. STATISTICAL METHODS

Incident cases of DefiniteMicrobiological Pulmonary TB disease meeting the third 
case definition.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
192
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
193
11.2. Secondary endpoints
IMMUNOGENICITY

Evaluation of CMI responses with respect to components of the study vaccine, in the 
safety and immune sub-cohort:

Determined by the frequency of M72-specific CD4+/CD8+ T-cells per million 
cells identified after in vitro stimulation, as expressing at least 2 immune markers 
among CD40L, IL-2, IFN-and TNF-. Determined by the frequency of M72-
specific CD4+/CD8+ T-cells per million cells identified after in vitro 
stimulation, as expressing any combination of immune markers among 
CD40L, IL-2, IFN-and TNF-.
Timepoints: prior to dose 1 (Day 0) and post-dose 2 (Day 60, Years 1, 2 and 3)
11.3. Tertiary endpoints 

Evaluation of CMI responses with respect to components of the study vaccine, in the 
safety and immune sub-cohort:

Determined by the frequency of M72-specific CD4+/CD8+ T-cells per million 
cells identified after in vitro stimulation, as expressing any combination of 
immune markers among CD40L, IL-2, IFN-and TNF-

QFTG test result. 
Time points: prior to dose 1 (Day 0), post dose 2 (Year 3)

Description of RNA expression profile signatures in selected samples as a 
correlate of risk to describe protective and non-protective immune responses 
after 2 doses of M72/AS01E.
Time points: Prior to dose 1 (Day 0), post dose 2 and when TB is diagnosed.
11.3. Determination of sample size
The primary objective is to demonstrate that the lower limit of the 95% Confidence 
interval90% CI of vaccine efficacy (VE), obtained from the Cox proportional hazards 
regression model (VE=1-estimated hazard ratio) associated to the M72/AS01E vaccine in 
preventing first episodes of definite pulmonary TB disease meeting the first case 
definition is >0.
Statistical analysis during the course of this study will include an interim analysis (IA) for 
futility, i.e. if a too low vaccine efficacy is observed at the time of the interim analysis, 
the trial will be stopped for futility. Therefore, no alpha adjustment is needed.
Using a logrank test with 80% power for a true VE of 70% (hazard ratio of 30%)and a 
two-sided 510% significance level, the number of cases required for a fixed sample 
design is 27 cases21cases, based on the assumption that the hazard rates are proportional. 
These results are obtained by the program PASS 2005.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
193
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
194
To obtain these 2721 cases in total at final efficacy analysis, assuming a mean yearly 
attack rate of 0.35 55% in the control group, 32 years of follow-up for each subject and a 
rate of loss ofto follow-up time of 1215% due to drop out over the 32 years period,
45003506 subjects need to be enrolled based on the logrank test and parameters described 
above.
Sample size considerations for the safety and immune sub-cohort:
Approximately 450 subjects will be enrolled in the safety and immune sub-cohort (225 
subjects in A planned follow-up time of 3 years for each treatment group) with 
upsubject allows to 150 subjects/contributing country (75 subjects in each treatment 
group)
Assuming a standard deviation of log10(value*) of 0.40**, as observed in previous 
studies, amitigate any lower than expected incidence rate and alternative to achieve a 
higher precision for the 95 % CI for log10(value*) of 0.052 or 0.092 will be obtained for 
a total sample size of 225 subjects vaccinated with M72/AS01E or 75 subjects vaccinated 
with M72/AS01E/country respectively.of the VE estimate at the final analysis. 
Precision of the log10(value*) is equal to half of the with of the 95% CI for 
log10(value*). The precision of the 95% CI and 95% CI can be derived by assuming 
various levels of the value*. Precision of the 95% CI for GMT for a sample size of 150
subjects and 450 subjects is presented in Table 26 and Table 27, respectively.
*GMT or median frequency of CD4 T cells expressing at least two immune markers 
among CD40L, IL-2, IFN-and TNF-
**A standard deviation around 0.40 for log10(GMT) and below 0.40 for log10(CD4 T 
cells expressing at least 2 immune markers) has been observed in previous studies. 
Tables 26 and 27 and also Section 11.5.2. have been deleted:
Table 26
Precision for the 95% CI for GMT obtained from the 95% CI build 
on log10(GMT) assuming various levels of GMT for a sample size of 75 subjects 
vaccinated with M72/AS01E
GMT
Log10(GMT)
precision for the 95% 
CI for log10(GMT)
95% CI for the GMT
precision for the 95% 
CI for the GMT
LL
UL
500
2.698970004
0.092
404.5479
617.9737
106.7129
1000
3
0.092
809.0959
1235.947
213.4258
2000
3.301029996
0.092
1618.192
2471.895
426.8515
3000
3.477121255
0.092
2427.288
3707.842
640.2773
4000
3.602059991
0.092
3236.384
4943.79
853.7031
5000
3.698970004
0.092
4045.479
6179.737
1067.129
6000
3.77815125
0.092
4854.575
7415.685
1280.555
CI: Confidence interval; GMT: Geometric Mean Titre; LL: Lower limit; UL: Upper limit
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
194
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
195
Table 27
Precision for the 95% CI for GMT obtained from the 95% CI build 
on log10(GMT) assuming various levels of GMT for a sample size of 225 subjects 
vaccinated with M72/AS01E
GMT
Log10(GMT)
precision for the 95% 
CI for log10(GMT)
95% CI for the GMT
precision for the 95% 
CI for the GMT
LL
UL
500
2.698970004
0.052
443.578
563.5987
60.01036
1000
3
0.052
887.156
1127.197
120.0207
2000
3.301029996
0.052
1774.312
2254.395
240.0414
3000
3.477121255
0.052
2661.468
3381.592
360.0622
4000
3.602059991
0.052
3548.624
4508.79
480.0829
5000
3.698970004
0.052
4435.78
5635.987
600.1036
6000
3.77815125
0.052
5322.936
6763.185
720.1243
CI: Confidence interval; GMT: Geometric Mean Titre; LL: Lower limit; UL: Upper limit
11.5.2. Modified Total vaccinated cohort for interim efficacy analysis
The modified TVC for interim efficacy analysis will include all subjects:

For whom two doses of study vaccines have been administered according to 
protocol (administration site and route)

Without randomisation failure

Without wrong replacment
Who did not present with TB disease, according to any case definition, during the
vaccination period (day of first vaccination up to 1 month post dose 2).
11.5.3. According-to-protocol cohort for analysis of immunogenicity
Without randomisation failure.
11.5.4. According-to-protocol cohort for analysis of efficacy
Without randomisation failure.
11.5.5. According-to-protocol cohort for analysis of QFTG status
The ATP cohort for analysis of QFTG status will include all subjects:

Who received two vaccinations according to protocol procedures within specified 
intervals.

For whom post vaccination QFTG blood samples are available.

Who did not receive a vaccine/medication that may lead to elimination of an ATP 
analysis.

Who did not present with a medical condition that may lead to elimination of an ATP 
analysis.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
195
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
196

For whom the randomization code has not been broken.

With a negative QFTG test result at baseline.

With no indeterminate QFTG test result at any time point.
11.7. Analysis of efficacy
Vaccine efficacy will be estimated from a Cox proportional hazard regression model 
(VE=1-hazard ratio) and 9590% CIs and Wald p-value will be derived. The primary 
analysis will be unadjusted but secondary analyses will evaluate the effect of potential 
covariates.
The lower limit of the 9590% two-sided confidence interval (CI) for the VE (using a Cox 
regression model) against first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the first case definition, is above 0%
If the primary objective is met, the confirmatory secondary objective will be evaluated 
with the following success criterion:
The lower limit of the 9590% two-sided confidence interval (CI) for the VE (using a Cox 
regression model) against first occurrence of Definite pulmonary TB disease not 
associated with HIV-infection, meeting the firstsecond case definition, is above 0%. 
For the tertiary efficacy analysis, the analysis will be based on the ATP cohort for 
analysis of Mtb infection. The vaccine efficacy will be estimated as 1- the Rate Ratio 
(RR) where the rate is defined as the number of subjects QFTG- positive (converters) at 
study end divided by the number of subjects QFTG- negative at baseline, in each group. 
These two proportions will be compared using the Fisher exact test. 
11.9.2. RNA expression profiling
In order to attempt to establish a correlate of risk for acquisition of infection, a systems 
biology approach will be used (refer to Section 6.7.4.2).
As exploratory, a comprehensive analysis of selected subjects’ immune responses 
following vaccination will be performed by RNA expression profiling using microarray 
analysis on whole blood samples. Microarray data will be analysed using bioinformatics 
approaches. The expected outcome of this analysis is to arrive at a RNA expression 
profile signature as a correlate of risk that could describe non-protective immune 
responses. Additional outcomes will shed further light on the immune responses induced 
by the vaccine.
Sample selection for microarray analysis could be based on the following comparisons:

Comparison of profiles of 'Breakthrough' cases, i.e. M72/AS01E vaccinated subjects 
with confirmed pulmonary TB meeting the first, second, third or fourth case 
definition with comparable group of M72/AS01E vaccinated subjects with no 
pulmonary TB. This could define a correlate of risk.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
196
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
197

Comparison of cases from M72/AS01E vaccinated and placebo groups will help 
deduce if the vaccine had an impact in the breakthrough cases, and if this analysis 
reveals the same signature in breakthrough cases from both groups.

Comparison of cases and non-cases in the placebo group as a negative control since 
there should be no difference.

Description of RNA expression profile signature to describe immune responses after 
dose 2 by comparing samples from vaccinated subjects with non-vaccinated subjects. 
This analysis is not linked to cases (e.g. comparison between the M72/AS01E 
vaccinated versus placebo).
11.9. Analysis of safety
Injection site swelling and redness will be analysed using a 3-grade evaluation system [0 
mm to 20 mm(grade 0); > 0 to 20 mm (grade 1); > 20 to 50 mm (grade 1); > 50 to 100
mm (grade 2); > 50100 mm (grade 3)]
11.12.1. Sequence of analyses
All analyses (including interim analysis) will be conducted on data as clean as possible.
The analyses will be performed stepwise:

An interim efficacy analysis for futility will be performed after approximately 10 
Xpert MTB/Rif positive pulmonary TB cases (aprroximately 40 % of the target 
events) in confirmed HIV-negative subjects have accumulated in the modified TVC 
for interim efficacy analysis, during the efficacy surveillance period starting 1 month 
post dose 2 (Day 60). If the study is stopped for futility, subjects will continue to be 
followed-up for safety up to 6 months post dose 2 and a study conclusion visit will 
be scheduled at the earliest convenient time point. All data (efficacy, safety and 
immunogenicity) collected up to last subject last visit (LSLV) will be cleaned, 
unblinded and analysed.
Analysis of efficacy will be performed when 27

Primary analysis of efficacy will be performed when 21 cases of definite pulmonary 
TB disease, meeting the first case definition, have accumulated in the ATP cohort for 
efficacy, during the efficacy surveillance period starting 1 month post dose 2 (Day 
60) or at the latest when all subjects have completed the Month 3624 visit. 
11.12.2. Statistical considerations for interim analyses
In order to avoid trial progression with a candidate vaccine with very low efficacy, an 
interim efficacy analysis for futility is planned, i.e. if a too low vaccine efficacy is 
observed at the time of the interim analysis, the trial will be stopped for futility. 
Therefore, no alpha adjustment is needed.
The analysis will be performed by a statistician external to the investigator group and 
“The Collaboration” (i.e. from a contract research organisation). The clinical team within 
GSK Biologicals and Aeras, all participating subjects, study site and GSK personnel 
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
197
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
198
directly involved in the conduct of the trial will remain blinded to the randomisation 
codes. The GSK statistician (and other personnel directly involved in the conduct of the 
trial) will not have access to the randomisation list and serology data.
The efficacy results at interim analysis will be looked at by the IDMC in closed session 
(with prohibited attendance by any member of GSK and Aeras and by any person 
involved in the conduct of the study). 
Stopping rules for futility will be defined in the statistical analysis plan for interim 
analysis.
12.1. Remote Data EntryeCRF instructions
Remote Data Entry (RDE),Inform™, a validated computer application, will be used as 
the method for data collection. 
12.2. Study Monitoring by “The Collaboration”
GSK and its partners in“The Collaboration” will monitor the study to verify that, 
amongst others, the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol, any other study 
agreements, GCP and all applicable regulatory requirements.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a RDEan eCRF review and a Source 
Document Verification (SDV). By SDV we understand verifying RDEeCRF entries by 
comparing them with the source data that will be made available by the investigator for 
this purpose.
The Source Documentation Agreement Form describes the source data for the different 
data in the RDEeCRF. This document should be completed and signed by the site 
monitor and investigator and should be filed in the monitor’s and investigator’s study file. 
Any data item for which the RDEeCRF will serve as the source must be identified, 
agreed and documented in the source documentation agreement form. 
For RDEeCRF, the monitor will mark completed and approved screens at each visit.
14. REFERENCES
World Health Organisation [WHO], 2011. Global Tuberculosis Control: Surveillance, 
Planning and Financing2013. Global tuberculosis report 2013;
http://www.who.int/tb/publications/global_report/en/, accessed 26 October 2011.02 
December 2013.
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
198
29-JAN-2014

CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
29-JAN-2014
199
APPENDIX B
CLINICAL LABORATORIES
Table 27
Outsourced laboratories 
Laboratory
Address
CEVAC - University of Gent
De Pintelaan, 185 Gent
Belgium
COVANCE
401 Terry Avenue North
Suite 200
Seattle, Washington 98109
USA
Central laboratories
BARC South Africa Pty Ltd
Napier Road POB 8475
2000 Johannesburg
Republic of South Africa
KEMRI/CDC Research Station, Kenya
Busia Road POB 1578-40100
Kisumu
Kenya
CIDRZ Zambia
Alick Nkhata Road
Kalingalinga Clinic Grounds
Lusaka
Zambia
 
CONFIDENTIAL
115616 (TUBERCULOSIS-018)
Protocol Amendment 5 Final
680e97c95ac54ffa4525253412affca36f653fc3
199
29-JAN-2014