An Epidemiology Study to Assess Plasmodium Falciparum Parasite Prevalence and Malaria Control Measures in Catchment Areas of Two Interventional Studies Pre- and Post RTS,S/AS01E Introduction (EPI MAL-002 and EPI-MAL-003) to Assess, in Field Conditions, Vaccine Benefit: Risk in Children in Sub Saharan Africa
Phase: PHASE4
Conditions: Malaria, Malaria Vaccines
Sponsor: GlaxoSmithKline

CONFIDENTIAL
14-SEP-2018
1
Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart,
Belgium
eTrack study number and 
Abbreviated Title
116682 (EPI-MALARIA-005 BOD AME)
Date of protocol
Final Version 1: 21 January 2014
Date of protocol amendment
Amendment 1 Final: 21 September 2016
Amendment 2 Final: 14 September 2018
Title
Epidemiology study of malaria transmission intensity 
in sub-Saharan Africa.
Detailed Title
An epidemiology study to assess Plasmodium 
falciparum parasite prevalence and malaria control 
measures in catchment areas of two interventional
studies pre- and post RTS,S/AS01E introduction 
(EPI-MAL-002 and EPI-MAL-003) to assess, in field 
conditions, vaccine benefit:risk in children in 
sub-Saharan Africa.
Co-ordinating author
, Freelance Science Writer for GSK 
Biologicals
Contributing authors
(Amended 14 September
2018)

,
, Global Epidemiology

, Clinical Manager Safety
Physician

, 

Clinical Laboratory Sciences-
SM Business and Decision Life Sciences for GSK
Biologicals

, Global Study Manager, external
consultant for GSK Biologicals

, Local Delivery Lead

, external consultant for
GSK Biologicals

, Clinical Manager Safety
Physician

, Clinical Immunology Manager

, Study Delivery Lead,
Synteract® for GSK Biologicals

, Lead Epidemiologist-Malaria,
Aixial for GSK Biologicals
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
1
14-SEP-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
2
eTrack study number and 
Abbreviated Title
116682 (EPI-MALARIA-005 BOD AME)
Detailed Title
An epidemiology study to assess Plasmodium 
falciparum parasite prevalence and malaria control 
measures in catchment areas of two interventional
studies pre- and post RTS,S/AS01E introduction 
(EPI-MAL-002 and EPI-MAL-003) to assess, in field 
conditions, vaccine benefit:risk in children in 
sub-Saharan Africa.
Contributing authors 
(Amended 14 September
2018)

, Senior Manager, 
Epidemiologist, ManiAfriCare for GSK 
Biologicals

, Study Statistician, 4clinics for 
GSK Biologicals

, Lead Epidemiologist-Malaria

, Senior Lead Epidemiologist-
Malaria

, Study Data Manager, TCS 
for GSK Biologicals

, Clinical & Epidemiology 
Project Lead, DDW Vaccines

,
 

, Clinical Epidemiologist, 
Bartech for GSK Biologicals

, Global Patent representative

, Oversight Data Manager

, Study Data Manager

, Study Statistician
GSK Biologicals’ protocol template for observational studies and interventional studies 
without administration of medicinal products as described in a research protocol based 
on the Protocol Document Standard version 14.1.2
© 2014-2018 GSK group of companies or its licensor.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
2
14-SEP-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
3
Protocol Amendment 2 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
116682 (EPI-MALARIA-005 BOD AME)
Date of protocol amendment
Amendment 2 Final: 14 September 2018
Detailed Title
An epidemiology study to assess Plasmodium 
falciparum parasite prevalence and malaria control 
measures in catchment areas of two interventional
studies pre- and post RTS,S/AS01E introduction 
(EPI-MAL-002 and EPI-MAL-003) to assess, in field 
conditions, vaccine benefit:risk in children in 
sub-Saharan Africa.
Sponsor signatory
François Roman
Clinical & Epidemiology Project Lead, DDW 
Vaccines
Signature
Date
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
3
14-SEP-2018
For Internal use only
 - ----------------Checksum----------------!Ver.!Created On -  - 
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb 2.0 9/25/2018 9:57:38 AM -  - 
---------------------------------------------------------------------------- - 

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
4
Protocol Amendment 2 Rationale
Amendment number:
Amendment 2
Rationale/background for changes:
A delay in the implementation of the RTS,S/AS01E vaccine in the 3 countries 
participating in the World Health Organisation (WHO)-led Malaria Vaccine 
Implementation Programme (MVIP) has resulted in a delay to the start of EPI-MAL-
003. As a consequence, EPI-MAL-005, being an ancillary study to EPI-MAL-003, will 
need to be extended in order to mirror the EPI-MAL-003 timeline. The need for an 
additional survey is the trigger for the second amendment of this protocol. Additional 
revisions to the protocol are listed below. 
1.
The current protocol – protocol amendment 1 - currently details 9 annual surveys 
with study duration of up to 9 years. The study will include at least 1 further 
annual survey, lasting for at least 10 years in total. Thus, the longest participating 
sites will perform the study for at least 10 years meaning 10 surveys, whilst some 
sites joining later will not perform as many surveys. Protocol text has been revised 
accordingly.
2.
Country and study site participation have changed during the course of the study
following WHO recommendations for pilot implementation of RTS,S/AS01E in 
settings with moderate-to-high transmission of malaria and WHO Regional Office 
for Africa selection for the initial introduction of RTS,S/AS01E in 3 countries 
(Ghana, Kenya and Malawi) through the MVIP. EPI-MAL-003 study site selection 
will be performed following Ministries of Health pre-selection and according to 
WHO guidance in the framework of the MVIP, to include 4 sites in each of the 3 
countries selected for the MVIP. Being an ancillary study to EPI-MAL-002 and 
EPI-MAL-003 studies, EPI-MAL-005 is/will be conducted in study sites 
conducting EPI-MAL-002 and/or EPI-MAL-003. Clarification on the countries 
and sites participating in the study has been provided.
3.
In response to a Corrective and Preventive Action following a Critical Quality 
Attributes audit conducted in Kintampo, Ghana, reference to study conduct in 
accordance with ‘Good Pharmacoepidemiology Practices (GPP) guidelines’ has 
been added to Section 5.1 ‘Regulatory and ethical considerations, including the 
informed consent process’ to align with STD-POL-GSKF-408, and additionally 
protocols EPI-MAL-002 and EPI-MAL-003.
4.
Vaccine eligible and ineligible subgroups were defined based on assumptions on 
the duration of follow-up of the EPI-MAL-005 study and date of vaccine 
implementation. This amendment primarily documents the extension of the study 
for at least 1 further survey. Furthermore, the date of implementation of the 
vaccine has yet to be confirmed. It is therefore not possible to apply these 
assumptions and the applicable text in Section 7.7.1.2 ‘By vaccine 
eligible/ineligible subgroup: Statistical analyses for vaccine association 
adjustments and association between vaccine and transmission’ has been revised.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
4
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
5
Protocol Amendment 2 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, with the terms of the study 
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 the site(s).
(Amended 14 September 2018)

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) or other 
applicable guidelines and all applicable regulatory requirements. 

To ensure that all persons assisting me with the study are adequately informed about 
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 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 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, 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
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
5
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
6
eTrack study number and 
Abbreviated Title
116682 (EPI-MALARIA-005 BOD AME)
Date of protocol amendment
Amendment 2 Final: 14 September 2018
Detailed Title
An epidemiology study to assess Plasmodium 
falciparum parasite prevalence and malaria control 
measures in catchment areas of two interventional
studies pre- and post RTS,S/AS01E introduction 
(EPI-MAL-002 and EPI-MAL-003) to assess, in field 
conditions, vaccine benefit:risk in children in 
sub-Saharan Africa.
Investigator name
Signature
Date
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
6
14-SEP-2018
For Internal use only
 - ----------------Checksum----------------!Ver.!Created On -  - 
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb 2.0 9/25/2018 9:57:38 AM -  - 
---------------------------------------------------------------------------- - 

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
7
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.
Study Contact for Reporting of a Serious Adverse Event (SAE) 
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 6.3.2.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
7
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
8
SYNOPSIS
Detailed Title
An epidemiology study to assess Plasmodium falciparum
parasite prevalence and malaria control measures in 
catchment areas of two interventional studies pre- and post 
RTS,S/AS01E introduction (EPI-MAL-002 and EPI-MAL-
003) to assess, in field conditions, vaccine benefit:risk in 
children in sub-Saharan Africa.
Rationale for the 
study 
(Amended 14 
September 2018)
Following the pivotal Phase III study of the candidate malaria 
vaccine RTS,S/AS01E (Malaria-055), two consecutive vaccine 
safety monitoring studies (EPI-MAL-002 and EPI-MAL-003) 
will be conducted to monitor incidence rates of meningitis, 
protocol defined adverse events of special interest (AESI), 
and of other adverse events leading to hospitalisation or death, 
in children. The first study, EPI-MAL-002, is a baseline
surveillance study prior to RTS,S/AS01E authorisation in the 
country; the second study, EPI-MAL-003, will more 
specifically monitor RTS,S/AS01E safety, as well as vaccine 
effectiveness and impact, and will only start when 
RTS,S/AS01E is authorised and implemented in the country. 
The World Health Organisation’s (WHO’s) Strategic 
Advisory Group of Experts (SAGE) on Immunization and the 
Malaria Policy Advisory Committee (MPAC) recommended 
pilot implementations of RTS,S/AS01E in children of 5–17 
months of age, in parts of 3-5 sub-Saharan African countries, 
administering 3 doses of the vaccine to children aged 5-9 
months of age in areas of moderate-to-high transmission of 
malaria with a fourth dose 15-18 months later. The first 
vaccine introduction is foreseen in 2018. The secondary 
endpoints of these studies also include monitoring the 
incidence of malaria disease as diagnosed during out-patient 
visits or hospitalisation. Health and Demographic 
Surveillance System (HDSS) (or equivalent system) sites1 in 
countries in sub-Saharan Africa will participate in these 
studies, enrolling approximately 30 000 children <5 years of 
age in EPI-MAL-002 and approximately 45 000 children <5 
years in EPI-MAL-003.
This epidemiology study (EPI-MAL-005) is planned to run in 
parallel with these two studies, enrolling from the same HDSS
(or equivalent system) populations. The primary objectives of 
this study are to produce longitudinal estimates of parasite 
prevalence in humans, and record malaria control measure 
                                                
1 Throughout the document, the terms of site, cluster and centre are used interchangeably, having the 
same meaning.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
8
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
9
usage in areas where EPI-MAL-002 and EPI-MAL-003 
studies will take place. As requested by WHO/JTEG, parasite 
prevalence as an indicator of malaria transmission intensity 
(MTI) may also contribute to the evidence base for vaccine 
recommendation in different MTI settings. It is expected that 
RTS,S/AS01E vaccine introduction through national 
immunisation systems will lead to a reduction in the incidence 
of malaria disease in vaccinated subjects in EPI-MAL-003 
when compared to baseline rates recorded in EPI-MAL-002. 
Annual fluctuations in malaria incidence occur as a result of 
changes in transmission intensity, which may be caused by 
changes in environmental factors such as rainfall or changes 
in usage of other malaria control interventions. Therefore, by 
taking into account these variations in MTI and malaria 
control intervention coverage, it will be possible to estimate 
more accurately the vaccine impact on clinical disease during 
EPI-MAL-003. These data will also allow for an assessment 
of any association between vaccination and gametocyte 
carriage in the 0-2 year age group, as an indicator of the 
potential effect of the vaccine on malaria transmission.
Outside of the controlled setting of a clinical trial, there is the 
risk that usage of malaria control interventions such as indoor
residual spraying and bednets may change following vaccine 
introduction. Vaccine introduction may lead to the 
misperception that other interventions are no longer required 
or may alter health seeking behaviours for fever, and thus are 
potential confounders of the effect of the vaccine on clinic-
identified malaria and therefore need to be monitored.
Although not yet considered as the gold standard, NAAT-
based (nucleic acid amplification test) techniques can detect 
infections of lower malaria parasite density and quantification 
of parasitaemia than is achievable by microscopy. 
Identification of gametocytes by microscopy is inherently 
challenging, thus their presence is often missed, even by 
highly trained technicians. Therefore, additional analysis of 
collected blood samples by NAAT will allow for the detection 
of lower density parasite infections and will be a more 
sensitive measure of changes in both parasite and gametocyte 
prevalence and density, thereby providing greater insight into 
potential changes upon vaccine implementation. This will also 
provide comparability of data collected in this study with the 
technique likely to be favoured in clinical trials in the future.
These data will enable a more complete assessment of the 
benefits and risks of vaccine introduction, and thereby more 
insight into the potential vaccine impact in 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
9
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
10
EPI-MAL-002/-003, by adjusting incidence data for overall 
changes in transmission and other malaria control intervention 
coverage, and assist generalisation of results to other 
populations.
Objectives
Co-Primary
In subjects aged 6 months to <10 years:

To obtain longitudinal estimates of P. falciparum parasite 
prevalence in order to characterise malaria transmission 
intensity in a standardised way at centres conducting the 
EPI-MAL-002 and EPI-MAL-003 studies before and 
after the introduction of the malaria vaccine 
RTS,S/AS01E in sub-Saharan Africa.

To obtain longitudinal estimates of the use of malaria 
control interventions in centres conducting the EPI-MAL-
002 and EPI-MAL-003 studies before and after the 
introduction of the malaria vaccine RTS,S/AS01E in sub-
Saharan Africa.
Secondary
In subjects aged 6 months to <10 years:

To estimate trends in longitudinal estimates of the 
parasite prevalence of P. falciparum by vaccine eligible 
or ineligible subgroups and overall.

To obtain longitudinal estimates of the prevalence of 
Plasmodium species other than P. falciparum; overall and 
by age group.

To estimate longitudinal trends in receipt and timing of 
the third dose of DTP/HepB/Hib and the first dose of 
measles EPI vaccines, at around 14 weeks and 9 months 
of age respectively, as appropriate by country.

To describe changes in care seeking behaviours for 
reported fever or malaria in the previous 14 days.

To assess within-site geographical heterogeneity in 
malaria transmission intensity.

To describe individual malaria prevention measures and 
risk factors for clinical malaria according to the parasite 
density observed.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
10
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
11
Tertiary
In subjects aged 6 months to <10 years:

To compare asexual and sexual (gametocyte) 
parasitaemia (qualitative and quantitative-density) in the 
RTS,S/AS01E vaccinated and unvaccinated subjects.

To compare asexual and sexual (gametocyte) 
parasitaemia (qualitative and semi-quantitative-density) 
when measured by microscopy or NAAT.
Study design
(Amended 14 
September 2018)

Type of design: A multi-centric, epidemiology 
longitudinal cross-sectional study at centres in sub-
Saharan Africa that are participating in GSK's EPI-MAL-
002 and EPI-MAL-003 studies.

There will be no study vaccine administered in this 
epidemiology study. 

Study population: Subjects 6 months to <10 years of age.

Type of study: self-contained

All medications that may influence malaria parasitaemia 
within 14 days prior to each survey will be recorded.

Axillary body temperature of all subjects at the time of 
the survey will be recorded. 

Biological samples: A capillary blood sample will be 
obtained for evaluation of malaria infection by blood 
slide and NAAT. In the event of measured fever at the 
time of the visit (axillary temperature ≥37.5°C) or fever 
reported in the last 24 hours or other symptoms/signs of 
clinical malaria, a rapid diagnostic test (RDT) will be 
conducted. If the RDT is positive, treatment will be given 
according to National guidelines. If a subject for whom 
no RDT was required is identified as being parasite 
positive following microscopy, National guidelines 
should be followed for clinical management of the 
subject.

Microscopy and NAAT will be used to evaluate the level 
of asexual and sexual parasitaemia.

Serious adverse events (SAEs) associated with the study 
procedure (capillary blood sampling) will be collected.

Using Geographic Information System (GIS) to 
determine geographical variability in MTI locally: Study 
areas will be mapped by villages using grid referencing. 
Subjects will be attributed to their village, however, to 
avoid PII (personally identifiable information); small 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
11
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
12
villages will be grouped when the number of participants 
is less than 10, so that it is not possible to identify one 
subject from one village. Therefore the study area will be 
divided into segments with a minimum of 10 subjects by 
segment regrouping villages by proximity if needed. 
Villages will be grouped at the time of random sampling 
of the study population. A map will be drawn showing 
the location of numbered segments, each numbered with 
a unique ID code and containing one or more villages. 
This map will NOT be submitted to GSK, but segments 
will be reported by their ID code and surface (km2) and 
subjects will be attributed to a segment code in the study 
database. 

Each study site will be requested annually to provide 
centre specific information about interventions from the 
malaria control programme in the study area to provide 
meteorological data for the study site such as rainfall and 
temperature. The information will be collected in the 
form of a questionnaire that will be recorded in a separate 
database to that for subject-specific data.

Data collection: Electronic Case Report Form (eCRF).

This study will involve up to 10 annual cross sectional 
surveys during malaria peak transmission with possible 
further extension, dependent on the duration of the 
EPI-MAL-002 and EPI-MAL-003 studies.

Duration of the study: up to 10 years with possible 
further extension, dependent on the duration of the 
EPI-MAL-002 and EPI-MAL-003 studies:

Epoch 001: Survey 1 at Year 1

Epoch 002: Survey 2 at Year 2

Epoch 003: Survey 3 at Year 3

Epoch 004: Survey 4 at Year 4

Epoch 005: Survey 5 at Year 5.

Epoch 006: Survey 6 at Year 6.

Epoch 007: Survey 7 at Year 7.

Epoch 008: Survey 8 at Year 8.

Epoch 009: Survey 9 at Year 9

Epoch 010: Survey 10 at Year 10
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
12
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
13
Synopsis Table 1
Study groups and epochs foreseen in the study (Amended 14 
September 2018)
Study 
Group
Age 
(Min/Max)
Epochs
Epoch 
001
Survey 
1
Epoch 
002
Survey 
2
Epoch 
003
Survey 
3
Epoch 
004
Survey 
4
Epoch 
005
Survey 
5
Epoch 
006
Survey 
6
Epoch 
007
Survey 
7
Epoch 
008
Survey 
8
Epoch 
009
Survey 
9
Epoch 010
Survey 10
Study 
site
6 months / 
9 years
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
Discussion of study 
design
(Amended 14 
September 2018)
Several methods of estimating MTI exist, including 
entomological inoculation rates (EIR), serological conversion 
rates (SCR) and blood parasite prevalence. The methodology 
and interpretation of SCR to classify the intensity of malaria is 
not commonly used yet, and although the EIR is a standard 
method, the measure is challenging and interpretation and 
comparability of setting may be difficult due to vector 
heterogeneity. Parasite prevalence, although requiring trained 
staff for slide reading, provides a standardised and relatively 
easy to implement method to assess MTI in study sites of varied 
transmission intensity and is therefore the method of choice in 
this study.
At least 10 annual cross sectional surveys at peak transmission 
will provide point estimates of parasite prevalence and 
subsequently a longitudinal assessment of the level of 
endemicity in each area covered by EPI-MAL-002 and 
EPI-MAL-003. Malaria transmission is highly seasonal so 
surveys will be carried out during the course of the rainy season
preferably when rains decrease, the period of highest malaria 
transmission. Annual fluctuations may be seen in all endemic 
areas and a longitudinal assessment will allow for a better 
appreciation of the scale and trend of this annual variation. 
Endemicity is dependent on several environmental factors 
including climate (rain and temperature), access to malaria care, 
and use of other malaria control interventions. Therefore, 
concurrent collection of data on these factors will be important 
for the interpretation of these study results and evaluation of 
vaccine impact. 
This study will be conducted in parallel to EPI-MAL-002 and 
EPI-MAL-003 in order to assess parasite prevalence and malaria 
control measures before and after vaccine introduction.
The age group for enrolment (6 months to <10 years) has been 
selected in this study as this permits analysis of parasite 
prevalence according to the WHO definition (2-9 years) and by 
the JTEG requested age (<5 years).
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
13
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
14
Number of 
subjects
Total expected sample size: Per site and by survey is a 
maximum of 400 subjects aged 6 months to <5 years and a 
maximum of 200 subjects aged 5 to <10 years.
Endpoints
(Amended 14 
September 2018)
Primary

Occurrence of P. falciparum parasitaemia (using 
microscopy)
Criteria/definitions: infection with P. falciparum
determined using a blood smear slide and determined using 
microscopy.

Occurrence of malaria control interventions
Criteria/definitions: malaria control interventions are 
mosquito net usage (including insecticide-treated nets 
[ITN] and long lasting insecticidal nets [LLIN]), indoor
residual spraying (IRS), seasonal malaria chemoprevention 
(SMC), intermittent preventative treatment in infants 
(IPTi), and ACT therapy received within the last 14 days.
Secondary

Demography and history characteristics
Criteria/definitions: gender, age, medical history.

Occurrence of Plasmodium species other than P. 
falciparum (using microscopy)
Criteria/definitions: infection with Plasmodium species 
other than P. falciparum determined using a blood smear 
slide and microscopy.

Occurrence of uptake and timing of the third dose of 
DTP/HepB/Hib and the first measles EPI vaccines
Criteria/definitions: vaccination record of receipt of dose 3 
of the DTP/HepB/Hib and the first dose of the measles EPI 
vaccines.

Occurrence of anti-malarial therapy
Criteria/definitions: any anti-malarial therapy received in 
the last 14 days.

Occurrence of measured fever
Criteria/definitions: any measured fever at time of visit 
(axillary temperature ≥37.5°C).

Occurrence of reported fever
Criteria/definitions: any reported fever occurring in the last 
24 hours.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
14
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
15

Occurrence of care seeking behaviour
Criteria/definitions: occurrence of visits to health providers 
following reported fever or malaria in the previous 14 days.

Geo-referencing characteristics
Criteria/definitions: positioning of the subject’s residence 
will be attributed to a segment with a unique ID from the 
grid referencing study area map in which the subject 
resides, where necessary, grouping small geographically 
proximate villages so that each segment has at least 10 
study subjects to avoid PII, and proceeding as far as 
geographically appropriate.

Occurrence of individual malaria prevention measures and 
risk factors
Criteria/definitions: malaria prevention measures are 
repellents and local herbs not specifically recommended by 
the national programme and risk factors are rural/urban 
area, construction material for the house, floor and roof,
type of eaves (open/closed), use of electricity and water 
source (distance from and type).
Tertiary

Occurrence of RTS,S/AS01E vaccine doses
Criteria/definitions: vaccination record of each dose 
received of the RTS,S/AS01E vaccine..

Occurrence of P. falciparum parasitaemia (using NAAT)
Criteria/definitions: detection of P. falciparum on dried 
blood spot and determined using NAAT.

Occurrence of sexual P. falciparum parasitaemia (using 
microscopy)
Criteria/definitions: detection of sexual P. falciparum using 
a blood smear slide and determined using microscopy.

Occurrence of sexual P. falciparum (using NAAT/QT-
NASBA)
Criteria/definitions: detection of sexual P. falciparum on 
dried blood spot and determined using NAAT.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
15
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
16
TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................22
GLOSSARY OF TERMS ...............................................................................................25
1.
INTRODUCTION....................................................................................................28
1.1.
Background ................................................................................................28
1.2.
Rationale for the study................................................................................28
2.
OBJECTIVES.........................................................................................................30
2.1.
Co-Primary objectives.................................................................................30
2.2.
Secondary objectives..................................................................................30
2.3.
Tertiary objectives.......................................................................................30
3.
STUDY DESIGN OVERVIEW ................................................................................31
3.1.
Discussion of study design .........................................................................32
4.
STUDY POPULATION...........................................................................................33
4.1.
Number of subjects / centres ......................................................................33
4.1.1.
Recruitment of study centres / investigators.................................34
4.1.2.
Sampling methods.......................................................................35
4.2.
Inclusion criteria for enrolment....................................................................36
4.3.
Exclusion criteria for enrolment...................................................................36
5.
CONDUCT OF THE STUDY ..................................................................................37
5.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................37
5.2.
Subject identification...................................................................................38
5.3.
General study aspects ................................................................................38
5.4.
Outline of study procedures ........................................................................38
5.5.
Detailed description of study procedures to be conducted at each 
survey visit..................................................................................................39
5.5.1.
Check inclusion and exclusion criteria .........................................39
5.5.2.
Informed consent.........................................................................39
5.5.3.
Collect demographic data ............................................................39
5.5.4.
Check and record medications/vaccinations ................................39
5.5.5.
Check and record relevant medical history ..................................40
5.5.6.
Assessment of body temperature ................................................40
5.5.7.
Collect data on malaria control interventions................................40
5.5.8.
Collect data on malaria prevention measures and risk 
factors..........................................................................................40
5.5.9.
Capillary blood sampling..............................................................40
5.5.10.
Site specific information collection ...............................................41
5.5.11.
Recording of SAEs ......................................................................41
5.5.12.
Study conclusion..........................................................................41
5.6.
Biological sample handling and analysis.....................................................42
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
16
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
17
5.6.1.
Use of specified study materials ..................................................42
5.6.2.
Biological samples.......................................................................43
5.6.3.
Laboratory assays .......................................................................43
6.
SAFETY.................................................................................................................44
6.1.
Safety definitions ........................................................................................44
6.1.1.
Definition of a serious adverse event ...........................................44
6.2.
Detecting and recording SAEs....................................................................45
6.2.1.
Time periods for detecting and recording SAEs ...........................45
6.2.2.
Evaluation of SAEs......................................................................46
6.2.2.1.
Active questioning to detect SAEs..............................46
6.2.2.2.
Assessment of the intensity of SAEs ..........................46
6.2.2.3.
Assessment of causality .............................................46
6.2.2.4.
Assessment of outcomes............................................47
6.3.
Reporting of SAEs ......................................................................................47
6.3.1.
Prompt reporting of SAEs related to study participation to 
GSK.............................................................................................47
6.3.2.
Contact information for reporting SAEs to GSK............................48
6.3.3.
Completion and transmission of SAEs reports related to 
study participation to GSK ...........................................................48
6.3.3.1.
Back-up system in case the electronic 
reporting system does not work..................................48
6.3.4.
Updating of SAE information after freezing of the subject’s 
eCRF...........................................................................................48
6.3.5.
Regulatory reporting requirements for SAEs................................49
6.4.
Follow-up of SAEs ......................................................................................49
6.4.1.
Follow-up during the study...........................................................49
6.4.1.1.
Follow-up after the subject is discharged from 
the study.....................................................................49
7.
STATISTICAL METHODS......................................................................................50
7.1.
Endpoints....................................................................................................50
7.1.1.
Primary endpoints........................................................................50
7.1.2.
Secondary endpoints ...................................................................50
7.1.3.
Tertiary endpoints........................................................................51
7.2.
Determination of sample size......................................................................51
7.2.1.
Children aged 6 months to <5 years ............................................52
7.2.2.
Children aged 2 to <10 years.......................................................53
7.2.3.
Children aged 5 to <10 years.......................................................53
7.3.
Cohorts for Analyses ..................................................................................54
7.3.1.
Total cohort..................................................................................54
7.3.2.
According-To-Protocol cohort ......................................................54
7.4.
Derived and transformed data.....................................................................55
7.5.
Analysis of demographics...........................................................................55
7.6.
Analysis of primary objectives.....................................................................55
7.7.
Analysis of secondary objectives ................................................................56
7.7.1.
Trends in parasite prevalence......................................................56
7.7.1.1.
Overall........................................................................56
7.7.1.2.
By vaccine eligible/ineligible subgroup: 
Statistical analyses for vaccine association 
adjustments and association between vaccine 
and transmission ........................................................56
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
17
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
18
7.7.1.2.1.
Annual fluctuations: vaccine 
ineligible subgroup..................................56
7.7.1.2.2.
Association between vaccine and 
parasite prevalence: vaccine 
eligible subgroup ....................................59
7.7.2.
Other prevalences and proportions..............................................61
7.7.3.
Within-site geographical heterogeneity and risk factors ...............61
7.8.
Analysis of tertiary objectives......................................................................61
7.9.
Interpretation of analyses............................................................................62
7.10.
Conduct of analyses ...................................................................................62
7.10.1.
Sequence of analyses..................................................................62
7.10.2.
Statistical considerations for interim analyses..............................62
8.
ADMINISTRATIVE MATTERS ...............................................................................62
8.1.
Electronic Case Report Form instructions...................................................62
8.2.
Study monitoring by GSK Biologicals..........................................................63
8.3.
Record retention .........................................................................................63
8.4.
Quality assurance.......................................................................................64
8.5.
Posting of information on publicly available registers and publication 
policy ..........................................................................................................64
8.6.
Provision of study results to investigators ...................................................65
9.
COUNTRY SPECIFIC REQUIREMENTS...............................................................65
10. REFERENCES.......................................................................................................66
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
18
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
19
LIST OF TABLES
PAGE
Table 1
Study groups and epochs foreseen in the study (Amended 14 
September 2018) ...................................................................................32
Table 2
List of study procedures to be conducted at each survey visit 
(Amended 14 September 2018) .............................................................38
Table 3
List of study procedures to be conducted during survey 
(Amended 14 September 2018) .............................................................39
Table 4
Biological samples .................................................................................43
..........................................................44
Table 6
Timeframes for submitting SAEs related to study participation to 
GSK .......................................................................................................47
Table 7
Approximated 95% CI limits around different values of observed 
parasite prevalence computed in function of several sample 
sizes.......................................................................................................52
Table 8
Power estimation to detect a certain RR (from 0.1 to 0.9) 
depending on different baseline prevalences (from 0.1 to 0.9) 
with a sample size of 360 subjects .........................................................57
Table 9
Power estimation to detect a certain RR (from 0.1 to 0.9) 
depending on different baseline prevalence with a sample size of 
240 subjects...........................................................................................58
Table 10
Outsourced laboratories.........................................................................71
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
19
14-SEP-2018
CCI

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
20
LIST OF FIGURES
PAGE
Figure 1
Illustration of the lower (LL) and upper (UL) limits of the 
approximated 95%CI built around observed parasite prevalences 
for a sample of 400 subjects...................................................................53
Figure 2
Illustration of the lower (LL) and upper (UL) limits of the 
approximated 95%CI built around observed parasite prevalences 
for a sample of 200 subjects...................................................................54
Figure 3
Illustration of the lower (LL) and upper (UL) limits of the exact 
95% CI built around both compared prevalences with a sample 
size of 360 subjects................................................................................57
Figure 4
Illustration of the power to detect a trend using the Cochran trend 
test, and based on a sample size of 360 subjects and an 
assumed decrease each year of 5%, 10% or 15% .................................59
Figure 5
Illustration of the lower (LL) and upper (UL) limits of the exact 
95% CI built around both compared prevalences with a sample 
size of 240 subjects................................................................................60
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
20
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
21
LIST OF APPENDICES
PAGE
APPENDIX A LABORATORY ASSAYS - DETERMINATION OF 
PARASITAEMIA BY MICROSCOPY......................................................67
APPENDIX B CLINICAL LABORATORIES ..................................................................71
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL...........................................................................................72
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
21
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
22
LIST OF ABBREVIATIONS
ACT
Artemisinin-based combination therapy
AESI
Adverse events of special interest
AMC
Academic Medical Center
ATP
According to protocol
CI
Confidence interval
CSP
Circumsporozoite protein
DTP
Diphtheria, tetanus, pertussis
eCRF
electronic Case Report Form
EIR
Entomological inoculation rates
EPI
Expanded program on immunization
GAPDH
Glyceraldehyde 3-phosphate dehydrogenase
GCP
Good Clinical Practice
GIS
Geographic Information System
GPP
Good Pharmacoepidemiology Practice
GSK
GlaxoSmithKline
HDSS
Health and Demographic surveillance system
HBsAg
Hepatitis B surface antigen
HepB
Hepatitis B
Hib
Heamophilus influenza type b
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IPTi
Intermittent preventative treatment in infants
IPTp
Intermittent preventative treatment in pregnancy
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
22
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
23
IRB
Institutional Review Board
IRS
Indoor residual spraying
ITN
Insecticide-treated net
JTEG
Joint technical expert group
LAR
Legally acceptable representative
LL
Lower limit
LLIN
Long lasting insecticidal nets
MPAC
Malaria Policy Advisory Committee
MTI
Malaria transmission intensity
MVI
PATH-Malaria Vaccine Initiative
MVIP
Malaria Vaccine Implementation Programme
NAAT
Nucleic acid amplification test
NC/NT-SAE
Non-communicable and non-traumatic serious adverse events
P. falciparum
Plasmodium falciparum
PII
Personally identifiable information
PRAC
Pharmacovigilance Risk Assessment Committee
QT-PCR
Quantitative polymerase chain reaction
QT-NASBA
Quantitative nucleic acid sequence-based amplification
RDT
Rapid diagnostic test
RR
Relative risk
RSE
Relative standard error
RT-PCR
Reverse transcriptase polymerase chain reaction
RTS
Hybrid protein comprising HBs (hepatitis B surface antibody) 
and CSP portions
RTS,S
Particulate antigen, containing both RTS and HBs proteins
SAE
Serious adverse event
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
23
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
24
SAGE
Strategic Advisory Group of Experts
SCR
Serological conversion rate
SDV
Source document verification
SMC
Seasonal malaria chemoprevention
SOP
Standard operating procedure
SPM
Study procedures manual
TFL
Tables, figures, listings
UL
Upper limit
WHO
World Health Organisation
(Amended 14 September 2018)
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
24
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
25
GLOSSARY OF TERMS
Anonymised data:
Information about an individual that GSK or a third party 
cannot reasonably attribute to the individual, or could 
only attribute to the individual by expending a 
disproportionate amount of time, effort or expense (e.g. 
de-identified or aggregated information). For the purpose 
of this policy, Key-Coded personally identifiable 
information shall not be considered Anonymised 
Information
Child in care:
A child who has been placed under the control or 
protection of an agency, organisation, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian.
Catchment area:
In this study, the catchment area is defined as the area of 
the HDSS (or equivalent system) study site participating 
in the EPI-MAL-002 and EPI-MAL-003 studies.
Care seeking behaviour:
When and where and at what time a child is taken for 
treatment for reported fever or malaria in the last 14 days.
DTP/HepB/Hib:
This refers to DTP, or DTP-Hep B (tetravalent) or DTP-
HepB-Hib (pentavalent).
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
Epidemiological study:
An observational or interventional study without 
administration of medicinal product(s) as described in a 
research protocol.
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. Typical examples of epochs are retrospective 
data collection and prospective data collection, etc.
eTrack:
GSK Biologicals’ tracking tool for clinical/ 
epidemiological trials.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
25
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
26
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Section 7.3 for details on criteria for evaluability).
First dose measles:
First measles containing vaccine.
Malaria control 
interventions:
Any intervention or control measure targeted at reducing 
malaria transmission or preventing malaria disease
[World Health Organisation, 2013]. This includes ITN, 
LLIN, IRS, SMC, IPTi, IPTp and ACTs.
Malaria prevention 
measures:
Any individual intervention used to prevent malaria and 
not specifically recommended by the malaria program.
This includes mosquito coils and local herbs. 
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. 
NB 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. 
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 the proper conduct of epidemiological studies 
at one or more investigational sites.
Study population:
Sample of population of interest.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the epidemiological study or a person 
about whom some medical information has been recorded 
in a database.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
26
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
27
Subjects at least 6 
months of age:
Six months old is defined as the same day as the date of 
birth occurring 6 calendar months later (e.g. if born on the 
8th January, a child becomes 6 months old on the 8th 
July).
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
Surveillance:
The ongoing systematic collection, collation, analysis, 
and interpretation of descriptive epidemiological health 
data on a specific disease. Surveillance can monitor 
incidence and/or prevalence, and/or inform about when 
and where health problems are occurring and who is 
affected.
Vaccine eligible age:
Vaccine eligible is defined as those subjects that on the 
basis of age would be eligible for RTS,S/AS01E
vaccination, even if vaccine is unavailable at the time of 
assessment. The age will depend on the label for
RTS,S/AS01E vaccination in the country. (At the time of 
study start, there will be no available vaccination with 
RTS,S/AS01E).
Vaccine ineligible age:
Vaccine ineligible is defined as those subjects that on the 
basis of age would be ineligible for RTS,S/AS01E
vaccination, regardless of vaccine availability at the time 
of assessment. The age will depend on the label for
RTS,S/AS01E vaccination in the country.
(Amended 14 September 2018)
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
27
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
28
1.
INTRODUCTION
1.1.
Background
GlaxoSmithKline (GSK) Biologicals in partnership with the PATH-Malaria Vaccine 
Initiative (MVI) is developing a Plasmodium falciparum malaria vaccine for routine 
immunisation of infants and children living in malaria-endemic areas.
GSK Biologicals has formulated the candidate pre-erythrocytic P. falciparum malaria 
vaccine, RTS,S/AS01E, which is currently under evaluation. The vaccine consists of 
sequences of the circumsporozoite (CS) protein and hepatitis B surface antigen (HBsAg) 
adjuvanted with AS01 (liposome formulation with MPL and QS21 immunostimulants). 
In the pivotal Phase III study (Malaria-055), efficacy of the candidate malaria vaccine 
RTS,S/AS01E against first or only episodes of clinical malaria over a follow-up of 12 
months in children aged 5-17 months was 55.8% (p<0.0001), and in coadministration 
with DTPwHepB/Hib vaccine at 6, 10 and 14 weeks of age was 31.3% (p<0.0001). Phase 
II and early Phase III data suggest it has an acceptable safety profile when given to young 
children and infants in co-administration with EPI routine vaccines. Please refer to the 
current Investigator Brochure for a review of the pre-clinical and clinical studies, and the 
potential risks and benefits of RTS,S/AS02 and RTS,S/AS01.
1.2.
Rationale for the study
Following the pivotal Phase III study of the candidate malaria vaccine RTS,S/AS01E
(Malaria-055), two consecutive vaccine safety monitoring studies (EPI-MAL-002 and 
EPI-MAL-003) will be conducted to monitor incidence rates of meningitis, protocol 
defined adverse events of special interest (AESI), and of other adverse events leading to 
hospitalisation or death, in children. The first study, EPI-MAL-002, is a baseline
surveillance study prior to RTS,S/AS01E authorisation in the country; the second study, 
EPI-MAL-003, will more specifically monitor RTS,S/AS01E safety, as well as vaccine 
effectiveness and impact, and will only start when RTS,S/AS01E is authorised and 
implemented in the country. The World Health Organisation’s (WHO’s) Strategic 
Advisory Group of Experts (SAGE) on immunization and the Malaria Policy Advisory 
Committee (MPAC) recommended pilot implementations of RTS,S/AS01E in children 
of 5–17 months of age, in parts of 3-5 sub-Saharan African countries, administering 
3 doses of the vaccine to children aged 5-9 months of age in areas of moderate-to-high 
transmission of malaria with a fourth dose 15-18 months later. The first vaccine 
introduction is foreseen in 2018. The secondary endpoints of these studies also include 
monitoring the incidence of malaria disease as diagnosed during out-patient visits or 
hospitalisation. Health and Demographic Surveillance System (HDSS) (or equivalent 
system) sites2 in countries in sub-Saharan Africa will participate in these studies,
                                                
2 Throughout the document, the terms of site, cluster and centre are used interchangeably, having the 
same meaning.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
28
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
29
enrolling approximately 30 000 children <5 years of age in EPI-MAL-002 and 
approximately 45 000 children <5 years in EPI-MAL-003.
This epidemiology study (EPI-MAL-005) is planned to run in parallel with these two 
studies, enrolling from the same HDSS (or equivalent system) populations. The primary 
objectives of this study are to produce longitudinal estimates of parasite prevalence in 
humans, and record malaria control measure usage in areas where EPI-MAL-002 and 
EPI-MAL-003 studies will take place. As requested by WHO/JTEG, parasite prevalence 
as an indicator of malaria transmission intensity (MTI) may also contribute to the 
evidence base for vaccine recommendation in different MTI settings. It is expected that 
RTS,S/AS01E vaccine introduction through national immunisation systems will lead to a 
reduction in the incidence of malaria disease in vaccinated subjects in EPI-MAL-003 
when compared to baseline rates recorded in EPI-MAL-002. Annual fluctuations in 
malaria incidence occur as a result of changes in transmission intensity, which may be 
caused by changes in environmental factors such as rainfall or changes in usage of other 
malaria control interventions. Therefore, by taking into account these variations in MTI 
and malaria control intervention coverage, it will be possible to estimate more accurately 
the vaccine impact on clinical disease during EPI-MAL-003. These data will also allow 
for an assessment of any association between vaccination and gametocyte carriage in the 
0-2 year age group, as an indicator of the potential effect of the vaccine on malaria 
transmission.
Outside of the controlled setting of a clinical trial, there is the risk that usage of malaria 
control interventions such as indoor residual spraying and bednets may change following 
vaccine introduction. Vaccine introduction may lead to the misperception that other 
interventions are no longer required or may alter health seeking behaviours for fever, and 
thus are potential confounders of the effect of the vaccine on clinic-identified malaria and 
therefore need to be monitored.
Although not yet considered as the gold standard, NAAT-based (nucleic acid 
amplification test) techniques can detect infections of lower malaria parasite density and 
give more accurate quantification of parasitaemia than is achievable by microscopy. 
Identification of gametocytes by microscopy is inherently challenging, thus their 
presence is often missed, even by highly trained technicians. Therefore, additional 
analysis of collected blood samples by NAAT will allow for the detection of lower 
density parasite infections and will be a more sensitive measure of changes in both
parasite and gametocyte prevalence and density, thereby providing greater insight into 
potential changes upon vaccine implementation. This will also provide comparability of 
data collected in this study with the technique likely to be favoured in clinical trials in the 
future.
These data will enable a more complete assessment of the benefits and risks of vaccine 
introduction, and thereby more insight into the potential vaccine impact in EPI-MAL-
002/-003, by adjusting incidence data for overall changes in transmission and other 
malaria control intervention coverage, and assist generalisation of results to other 
populations.
(Amended 14 September 2018)
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
29
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
30
2.
OBJECTIVES
2.1.
Co-Primary objectives
In subjects aged 6 months to <10 years:

To obtain longitudinal estimates of P. falciparum parasite prevalence in order to 
characterise malaria transmission intensity in a standardised way at centres 
conducting the EPI-MAL-002 and EPI-MAL-003 studies before and after the 
introduction of the malaria vaccine RTS,S/AS01E in sub-Saharan Africa.

To obtain longitudinal estimates of the use of malaria control interventions in centres 
conducting the EPI-MAL-002 and EPI-MAL-003 studies before and after the 
introduction of the malaria vaccine RTS,S/AS01E in sub-Saharan Africa.
Refer to Section 7.1.1 for the definition of the primary endpoints.
2.2.
Secondary objectives
In subjects aged 6 months to <10 years:

To estimate trends in longitudinal estimates of the parasite prevalence of P. 
falciparum by vaccine eligible or ineligible subgroups and overall.

To obtain longitudinal estimates of the prevalence of Plasmodium species other than 
P. falciparum; overall and by age group.

To estimate longitudinal trends in receipt and timing of the third dose of 
DTP/HepB/Hib and the first dose of measles EPI vaccines, at around 14 weeks and 9 
months of age respectively, as appropriate by country.

To describe changes in care seeking behaviours for reported fever or malaria in the 
previous 14 days.

To assess within-site geographical heterogeneity in malaria transmission intensity.

To describe individual malaria prevention measures and risk factors for clinical 
malaria according to the parasite density observed.
Refer to Section 7.1.2 for the definition of the secondary endpoints.
2.3.
Tertiary objectives
In subjects aged 6 months to <10 years:

To compare asexual and sexual (gametocyte) parasitaemia (qualitative and 
quantitative-density) in the RTS,S/AS01E vaccinated and unvaccinated subjects.

To compare asexual and sexual (gametocyte) parasitaemia (qualitative and semi-
quantitative-density) when measured by microscopy or NAAT.
Refer to Section 7.1.3 for the definition of the tertiary endpoints.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
30
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
31
3.
STUDY DESIGN OVERVIEW
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 5.4), are essential and required for 
study conduct. 

Type of design: A multi-centric, epidemiology longitudinal cross-sectional study at 
centres in sub-Saharan Africa that are participating in GSK's EPI-MAL-002 and EPI-
MAL-003 studies.

There will be no study vaccine administered in this epidemiology study. 

Study population: Subjects 6 months to <10 years of age.

Type of study: self-contained

All medications that may influence malaria parasitaemia within 14 days prior to each 
survey will be recorded.

Axillary body temperature of all subjects at the time of the survey will be recorded. 

Biological Samples: A capillary blood sample will be obtained for evaluation of 
malaria infection by blood slide and NAAT. In the event of measured fever at the 
time of the visit (axillary temperature ≥37.5°C) or fever reported in the last 24 hours
or other symptoms/signs of clinical malaria, a rapid diagnostic test (RDT) will be 
conducted. If the RDT is positive, treatment will be given according to National 
guidelines. If a subject for whom no RDT was required is identified as being parasite 
positive following microscopy, National guidelines should be followed for clinical 
management of the subject.

Microscopy and NAAT will be used to evaluate the level of asexual and sexual 
parasitaemia.

Serious adverse events (SAEs) associated with the study procedure (capillary blood 
sampling) will be collected.

Using Geographic Information System (GIS) to determine geographical variability in 
MTI locally: Study areas will be mapped by villages using grid referencing. Subjects 
will be attributed to their village, however, to avoid PII (personally identifiable 
information), small villages will be grouped when the number of participants is less 
than 10, so that it is not possible to identify one subject from one village. Therefore 
the study area will be divided into segments with a minimum of 10 subjects by 
segment regrouping villages by proximity if needed. Villages will be grouped at the 
time of random sampling of the study population. A map will be drawn showing the 
location of numbered segments, each numbered with a unique ID code and 
containing one or more villages. This map will NOT be submitted to GSK, but 
segments will be reported by their ID code and surface (km2) and subjects will be 
attributed to a segment code in the study database.

Each study site will be requested annually to provide centre specific information 
about interventions from the malaria control program in the study area and, if 
facilities are available, to provide meteorological data for the study site such as 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
31
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
32
rainfall and temperature. The information will be collected in the form of a 
questionnaire that will be recorded in a separate database to that for subject-specific 
data.

Data collection: Electronic Case Report Form (eCRF).

This study will involve up to 10 annual cross sectional surveys during malaria peak 
transmission with possible further extension, dependent on the duration of the 
EPI-MAL-002 and EPI-MAL-003 studies.

Duration of the study: up to 10 years with possible further extension, dependent on 
the duration of the EPI-MAL-002 and EPI-MAL-003 studies:

Epoch 001: Survey 1 at Year 1

Epoch 002: Survey 2 at Year 2

Epoch 003: Survey 3 at Year 3

Epoch 004: Survey 4 at Year 4

Epoch 005: Survey 5 at Year 5.

Epoch 006: Survey 6 at Year 6.

Epoch 007: Survey 7 at Year 7.

Epoch 008: Survey 8 at Year 8.

Epoch 009: Survey 9 at Year 9

Epoch 010: Survey 10 at Year 10
(Amended 14 September 2018)
Table 1
Study groups and epochs foreseen in the study (Amended 14 
September 2018)
Study 
Group
Age 
(Min/Max)
Epochs
Epoch 
001
Survey 
1
Epoch 
002
Survey 
2
Epoch 
003
Survey 
3
Epoch 
004
Survey 
4
Epoch 
005
Survey 
5
Epoch 
006
Survey 
6
Epoch 
007
Survey 
7
Epoch 
008
Survey 
8
Epoch 
009
Survey 
9
Epoch 
010
Survey 
10
Study 
site
6 months / 
9 years
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
3.1.
Discussion of study design
Several methods of estimating MTI exist, including entomological inoculation rates 
(EIR), serological conversion rates (SCR) and blood parasite prevalence. The 
methodology and interpretation of SCR to classify the intensity of malaria is not 
commonly used yet, and although the EIR is a standard method, the measure is 
challenging and interpretation and comparability of setting may be difficult due to vector 
heterogeneity. Parasite prevalence, although requiring trained staff for slide reading, 
provides a standardised and relatively easy to implement method to assess MTI in study 
sites of varied transmission intensity and is therefore the method of choice in this study.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
32
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
33
At least 10 annual cross sectional surveys at peak transmission will provide point 
estimates of parasite prevalence and subsequently a longitudinal assessment of the level 
of endemicity in each area covered by EPI-MAL-002 and EPI-MAL-003. Malaria 
transmission is highly seasonal so surveys will be carried out during the course of the 
rainy season preferably when rains decrease, the period of highest malaria transmission. 
Annual fluctuations may be seen in all endemic areas and a longitudinal assessment will 
allow for a better appreciation of the scale and trend of this annual variation. Endemicity 
is dependent on several environmental factors including climate (rain and temperature), 
access to malaria care, and use of other malaria control interventions. Therefore, 
concurrent collection of data on these factors will be important for the interpretation of 
these study results and evaluation of vaccine impact.
(Amended 14 September 2018)
This study will be conducted in parallel to EPI-MAL-002 and EPI-MAL-003 in order to 
assess parasite prevalence and malaria control measures before and after vaccine 
introduction.
The age group for enrolment (6 months to <10 years) has been selected in this study as 
this permits analysis of parasite prevalence according to the WHO definition [WHO,
1963] (2-9 years) and by the JTEG requested age (<5 years).
4.
STUDY POPULATION
4.1.
Number of subjects / centres
Subjects 6 months to <10 years of age living in HDSS (or equivalent system) catchment 
areas of the sites participating in the EPI-MAL-002 and EPI-MAL-003 studies are 
eligible for enrolment (see Section 4.1.1). Subjects already enrolled in EPI-MAL-002 
and EPI-MAL-003 are eligible for participation in this study.
(Amended 14 September 2018)
Each study site will enroll approximately 600 subjects per survey. These subjects will be 
selected at random from the HDSS (or equivalent system) population listings prepared at 
each site. The selection process will be repeated every year meaning that the subjects will 
be different in each cross-sectional survey except if they are re-selected in a subsequent 
survey by chance. The population listings generated from the demographic surveillance 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
33
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
34
will allow for sampling of the required subjects according to stratification by age group 
as follows (all subject numbers are approximately plus or minus 5 children): 

60 children aged 6 months to <1 year

120 children aged 1 year

120 children aged 2 years

50 children aged 3 years

50 children aged 4 years

40 children aged 5 years

40 children aged 6 years

40 children aged 7 years

40 children aged 8 years

40 children aged 9 years
Therefore, the total expected sample size per site and by survey is a maximum of 400 
subjects aged 6 months to <5 years and a maximum of 200 subjects aged 5 to <10 years.
Refer to Section 7.2 for a detailed description of the criteria used in the estimation of 
sample size.
4.1.1.
Recruitment of study centres / investigators 
The ancillary EPI-MAL-005 study will be conducted in sites defined in the 
EPI-MAL-002 and EPI-MAL-003 protocols. At the time of original protocol 
finalisation, identified study sites were located in Burkina Faso, Ghana, Kenya, Senegal, 
and Tanzania.
Following the WHO’s SAGE on immunization and the MPAC recommendations of pilot 
implementations of RTS,S/AS01E in 3-5 distinct settings in sub-Saharan Africa restricted 
to moderate-to-high transmission of malaria, site selection in some of the initially chosen 
EPI-MAL-002, EPI-MAL-003 and EPI-MAL-005 study sites located in low endemicity 
settings (i.e. in Senegal and Tanzania) had to be terminated. In April 2017, the WHO 
Regional Office for Africa announced that the RTS,S/AS01E vaccine will be first 
introduced in 3 countries (Ghana, Kenya and Malawi) through the Malaria Vaccine 
Implementation Programme (MVIP). Selection of the clusters that are/will participate 
in GSK’s baseline, Phase IV and ancillary studies (i.e. EPI-MAL-002, EPI-MAL-003 
and EPI-MAL-005, respectively), being fully embedded in the MVIP, depends on the 
cluster identification process led by the Ministries of Health according to WHO 
guidance. They have been, or will be, selected as follows:

Sites have been, or will be, selected from the 3 countries where the RTS,S/AS01E
vaccine will be implemented (Ghana, Kenya and Malawi). Burkina Faso sites that 
started EPI-MAL-005 will early terminate the conduct of the study following 
Survey 4; data from these sites will be presented in the interim report planned 
following Survey 5.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
34
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
35

As currently planned in the MVIP and according to WHO guidance, 4 study sites 
(corresponding to 4 clusters of the MVIP) in each of the 3 countries selected for 
the RTS,S/AS01E pilot implementation programme (12 study sites/clusters in total) 
are planned to be part of EPI-MAL-005. 

Of note, all study sites are submitted to a comprehensive scientific and operational 
study site assessment conducted by GSK, which will determine study feasibility in 
those sites.
In summary, selection of sites will be performed in EPI-MAL-002 and EPI-MAL-003
studies following Ministries of Health pre-selection and according to WHO guidance, 
to include 4 sites in each of the 3 countries selected for the MVIP. EPI-MAL-005 
is/will be conducted in study sites conducting EPI-MAL-002 and/or EPI-MAL-003.
(Amended 14 September 2018)
4.1.2.
Sampling methods
All participating centres will have a HDSS (or equivalent system) in place. In general, 
any variation in sampling procedure should follow as closely as possible the Guidelines 
of the [Roll Back Malaria Monitoring and Evaluation Reference Group, 2005]. The 
following steps serve as an example of a sampling method.
1.
Generate a list from the HDSS (or equivalent system) database of all children aged 6 
months to <10 years.
2.
Order the list of subjects by age, then by village within each age category.
3.
Divide the total number of children for each age category by the sample needed in 
that age category, including 10% or more, according to local variations, extra to 
reflect non-response/refusal. This gives the size of the sequence for that age category 
(e.g. every xth subject, where x=total number of children for age category/number to 
be selected in the age category).
4.
If the sequence (x) is 20 for example, select randomly a first subject among the 20 
first subjects.
5.
From this subject, pick every 20th subject until the end of that age category.
6.
Repeat steps 3-5 for each age category.
If a subject is not found during the study team visit (e.g. possible migration, 
hospitalisation, …) three attempts should be made to reach the subject at home to
minimise sampling bias, before the subject’s enrolment is abandoned. It is likely there 
will be some non-response as a result of migration or refusal by the parents/LAR and this 
has been taken into account in the sample size calculation. 
The household of each randomly selected subject should be visited by a study team that 
will be able to carry out the protocol procedures in field conditions e.g. informed consent
form (ICF) procedure, blood sample collection, questionnaire administration and data 
recording. In order to enable logistically feasible, but methodologically rigorous,
sampling the field team should work their way through the sampling at their own 
discretion in a way that minimises travel to and between sampling points, e.g. in order of 
proximity of subjects or geographical sequence.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
35
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
36
Each study site will enrol approximately 600 subjects per survey. To allow for 10% 
non-response 660 subjects should therefore be randomly selected from the HDSS (or 
equivalent system) database distributed over all age categories as described in 
Section 4.1. In order to meet enrolment timelines, the sampling scheme could be 
implemented in the following fashion: 3 survey teams, each comprising two individuals, 
can be in the field 5 days per week for a period of 8 weeks. Each day in the field, a 
minimum of 5 subjects should be visited per team. Therefore, over the course of the 8 
weeks, a minimum of 600 visits can be made. Though more time may be required if large 
numbers of subjects require repeat visits, teams may achieve more visits per day than 
proposed here if subjects are in close proximity or in the same household.
4.2.
Inclusion criteria for enrolment
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
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’ whose parent(s)/Legally Acceptable Representative(s) [LAR(s)], in the 
opinion of the investigator, can and will comply with the requirements of the 
protocol.

A male or female 6 months to <10 years of age at the time of survey.

Signed informed consent or thumbprinted and witnessed informed consent obtained 
from the parent(s)/LAR(s) of the child.
4.3.
Exclusion criteria for enrolment
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise 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:

Child in care
Please refer to the glossary of terms for the definition of child in care.

Current active participation in any trial involving administration of an investigational 
malaria vaccine or malaria drug.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
36
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
37
5.
CONDUCT OF THE STUDY
5.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), Guidelines for Good Pharmacoepidemiology Practices (GPP) [ISPE, 
2015], other applicable guidelines, all applicable subject privacy requirements and the 
guiding principles of the Declaration of Helsinki.
(Amended 14 September 2018)
The study has been designed and will be conducted in accordance with the ICH 
Harmonised Tripartite Guideline for clinical investigation of medicinal products in the 
paediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favourable opinion/approval to conduct the study prior to a site initiating 
the study in that country or will document that neither a favourable opinion nor an 
approval to conduct the study is needed.
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’s parent(s)/LAR(s) informed consent and subject informed assent, as 
appropriate.

Investigator reporting requirements as stated in the protocol. 
GSK Biologicals will provide full details of the above procedures to the investigator, 
either verbally, in writing, or both. 
Freely given and written or thumbprinted informed consent must be obtained from each 
subject’s parent(s)/LAR(s) or the impartial witness and subject informed assent, as 
appropriate, prior to participation in the study. 
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the applicable ICH GCP or other applicable guidelines, and GSK Biologicals required 
elements. While it is strongly recommended that this model ICF 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
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
37
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
38
5.2.
Subject identification
Subject numbers will be assigned sequentially to subjects consenting to participate/to be 
included in the study, according to the range of subject numbers allocated to each study 
centre.
5.3.
General study aspects
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM provides the 
investigator and the site personnel with administrative and detailed technical information 
that does not impact the safety of the subjects.
5.4.
Outline of study procedures
Table 2 details study procedures to be conducted during the study.
Table 2
List of study procedures to be conducted at each survey visit
(Amended 14 September 2018)
Epoch
Epoch 
001
Epoch 
002
Epoch 
003
Epoch 
004
Epoch 
005
Epoch 
006
Epoch 
007
Epoch 
008
Epoch 
009
Epoch 
010
Study Group1
Survey 
1
Survey 
2
Survey 
3
Survey 
4
Survey 
5
Survey 
6
Survey 
7
Survey 
8
Survey 
9
Survey 
10
Timepoint
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9
Year 
10
Informed consent
●
●
●
●
●
●
●
●
●
●
Check inclusion/exclusion criteria
●
●
●
●
●
●
●
●
●
●
Record demographic details
●
●
●
●
●
●
●
●
●
●
Record subject’s vaccination 
status2
●
●
●
●
●
●
●
●
●
●
Record any anti-malarial 
medication or other medication 
received within the previous 14 
days
●
●
●
●
●
●
●
●
●
●
Record relevant medical history 
(hospitalisation, reported fever, 
and care seeking behaviour)
●
●
●
●
●
●
●
●
●
●
Record axillary body temperature
●
●
●
●
●
●
●
●
●
●
Record malaria control measures 
used in the household
●
●
●
●
●
●
●
●
●
●
Record malaria prevention and 
risk factors
●
●
●
●
●
●
●
●
●
●
Take capillary blood sample3
●
●
●
●
●
●
●
●
●
●
Assessment of RDT4
●
●
●
●
●
●
●
●
●
●
Study conclusion
●
●
●
●
●
●
●
●
●
●
Footnotes to Table 2:
● is used to indicate a study procedure that requires documentation in the individual eCRF
1 New sites will join the study after survey 3, depending on when they are included in EPI-MAL-002/-003. The total 
surveys at these new sites will therefore be less than 10.
2 RTS,S/AS01 and 3rd dose DTP/HepB/Hib and first dose measles EPI vaccinations, only
3 Capillary blood sample for determination of parasite prevalence (blood slides and NAAT by filter paper)
4 In the event of measured fever at time of visit (axillary temperature ≥37.5°C) or fever reported in last 24 hours or 
other symptoms/signs of clinical malaria, a rapid diagnostic test (RDT) will be conducted using capillary blood sample 
taken for blood slide preparation.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
38
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
39
Table 3
List of study procedures to be conducted during survey (Amended 
14 September 2018)
Epoch
Epoch 
001
Epoch 
002
Epoch 
003
Epoch 
004
Epoch 
005
Epoch 
006
Epoch 
007
Epoch 
008
Epoch 
009
Epoch 
010
Study Group
Survey 
1
Survey 
2
Survey 
3
Survey 
4
Survey 
5
Survey 
6
Survey 
7
Survey 
8
Survey 
9
Survey 
10
Timepoint
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9
Year 
10
Site specific information 
collection - Meteorological data1
●
●
●
●
●
●
●
●
●
●
Site specific information 
collection –
Malaria Control Programme
●
●
●
●
●
●
●
●
●
●
● is used to indicate a study procedure that requires documentation in the individual eCRF.
1 Availability of meteorological data will be based on the site having the weather station. All sites received weather 
stations either post Survey 1 or 2 or at study start for the new sites.
5.5.
Detailed description of study procedures to be conducted at 
each survey visit
5.5.1.
Check inclusion and exclusion criteria 
Check all applicable inclusion and exclusion criteria as described in Sections 4.2 and 4.3
before enrolment. 
5.5.2.
Informed consent 
The signed/witnessed/thumbprinted informed consent of the subject’s parent(s)/LAR(s) 
must be obtained before study participation. The signed informed assent of a subject 
below the age of consent (i.e., minor) should be obtained in addition to the signed 
informed consent by his/her parent(s)/LAR(s) according to local rules and regulations. 
Refer to Section 5.1 for the requirements on how to obtain informed consent and assent, 
as appropriate. 
5.5.3.
Collect demographic data
Record demographic data (date of birth, gender) and study area identification in the 
subject’s eCRF.
5.5.4.
Check and record medications/vaccinations
Record RTS,S/AS01E (all doses) and other vaccinations (i.e. 3rd dose DTP/HepB/Hib and
first dose measles EPI vaccinations) administered, including dates. The vaccination status 
will be recorded in the eCRF.
Record use of any anti-malarial or any other medication within 14 days prior to study 
visit. Data to be verified from health card or medical prescription document.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
39
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
40
5.5.5.
Check and record relevant medical history
Record details of relevant medical history in the eCRF:

Obtain reported history of temperature within the last 24 hours by interview

Obtain details for hospitalisation for malaria within the last 3 months by interview 
and/or review of subject’s health card

Obtain details of visits to health provider for fever or malaria treatment in the 
previous 14 days by interview and/or review of subject’s health card.
5.5.6.
Assessment of body temperature
The following information must be recorded in the eCRF:

Axillary temperature as measured by a digital thermometer at the time of the survey.
5.5.7.
Collect data on malaria control interventions
Record the following malaria control measures in the subject’s eCRF:

Indoor residual spraying (IRS), mosquito net usage (including insecticide-treated 
nets [ITN] and long lasting insecticidal nets [LLIN]), seasonal malaria 
chemoprevention (SMC), intermittent preventive treatment in infants (IPTi), and all 
anti-malaria therapy received within the last 14 days.
(Amended 14 September 2018)
5.5.8.
Collect data on malaria prevention measures and risk factors
Record the following information in the subject’s eCRF:

Repellents and local herbs used, rural/urban area, construction material for the house, 
floor, and roof, type of eaves (open/closed), use of electricity, and water source
(distance from and type).
5.5.9.
Capillary blood sampling 
A capillary blood sample collected by finger/heel prick, will be taken during the study 
visit for the assessment of parasitaemia (see Section 5.6.2). The following biological 
samples will be taken at each survey visit:

Blood for asexual and sexual (gametocyte) microscopy (2 slides, approximately 2 
drops on each microscope slide).
Preparation of microscopic slides in the field or at the laboratory is at the discretion 
of the study site staff. For microscopic slide preparation in the field, approximately 2 
drops of blood will be applied directly on each microscopy slide. For microscopic 
slide preparation in the laboratory, the blood sample will be collected in provided 
microtubes for transport to the laboratory.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
40
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
41

Blood for asexual and sexual (gametocyte) NAATs (approximately 2 drops on filter 
paper).
In the event of measured fever at the time of the visit (axillary temperature ≥37.5°C) or 
fever reported in last 24 hours or other symptoms/signs of clinical malaria, a RDT will 
also be conducted using the capillary blood sample
Refer to the Module on Biospecimen Management in the SPM for general handling of 
blood samples.
5.5.10.
Site specific information collection
Centre specific information about meteorological data such as rainfall, temperature and 
humidity, if available, will be collected by questionnaire and recorded in a separate 
database to that for subject-specific data. All sites received weather stations either post 
Survey 1 or 2 or at study start for the new sites. 
Centre specific information about interventions from the malaria control programme in 
the study area, such as bednet usage (including ITN and LLIN), IRS, ACT, SMC, IPTp 
and IPTi, will be collected by questionnaire and recorded in a separate database to that 
for subject-specific data.
(Amended 14 September 2018)
5.5.11.
Recording of SAEs
Capillary blood sampling is the only invasive procedure involved in this study. SAEs 
related to this procedure will be recorded.

Refer to Section 6.2 for procedures for the investigator to record SAEs. Refer to 
Section 6.3 for guidelines on how to submit SAE reports to GSK Biologicals.

The subjects’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should the subjects manifest any signs or symptoms they perceive as 
serious. 
5.5.12.
Study conclusion
The investigator will:

Review all the data collected to ensure accuracy and completeness 

Complete the Study Conclusion screen in the eCRF.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
41
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
42
5.6.
Biological sample handling and analysis
Please refer to the SPM for details of biospecimen management (handling, storage and 
shipment).
Samples will not be labelled with information that directly identifies the subjects but will 
be coded with the identification number for the subject (subject number). 

Collected samples will be used for protocol mandated research. In addition, these 
samples may be used to perform research related to the improvement, development 
and quality assurance of the laboratory tests described in this protocol. This may 
include the management of the quality of these tests, the maintenance or 
improvement of these tests, the development of new test methods, as well as making 
sure that new tests are comparable to previous methods and work reliably.

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed will be invited to give another specific 
consent when signing the Informed Consent Form to allow GSK or a contracted 
partner to use the samples for future research including development of tests and 
their quality assurance. Future research will be subject to the laws and regulations in 
the respective countries and will only be performed once an independent Ethics 
Committee or Review Board has approved this research.
Information on further investigations and their rationale can be obtained from GSK
Biologicals.
Any sample testing will be done in line with the consent of the subject’s 
parent(s)/LAR(s). 
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit/contact), 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.
5.6.1.
Use of specified study materials
When materials are provided by GSK Biologicals, it is MANDATORY that all 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 7.3 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 does not provide material for collecting and storing samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
42
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
43
5.6.2.
Biological samples
Table 4
Biological samples
Sample type
Quantity
Timepoint
Whole blood
Approximately 1 drop
(RDT assessment)*
Survey Visit
Whole blood
Approximately 4 drops; 1 drop for the thin smear and up to 3 
drops for the thick smear (merozoite and gametocyte 
microscopy assessment)
Survey Visit
Whole blood
2 to 3 drops; filter paper collection 
(parasite and gametocyte NAAT assessment)
Survey Visit
RDT = Rapid Diagnostic Test
NAAT = Nucleic Acid Amplification Test
*In the event of measured fever at the time of the visit (axillary temperature ≥37.5°C) or fever reported in last 24 hours 
or other symptoms/signs of clinical malaria.
5.6.3.
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.
In the event of fever measured at time of visit (axillary temperature ≥37.5°C) or reported 
fever in last 24 hours or other symptoms/signs of clinical malaria, a RDT will be 
conducted. The clinical management of subjects presenting with malaria as identified by 
RDT or microscopy will follow National guidelines. Subjects will receive appropriate 
care according to standard clinical practice.
All blood slides with thick and thin smears will be made in duplicate. One slide with 
thick and thin smears will be sent for storage to a GSK dedicated laboratory facility and 
the remaining slide will be stored at the study site. For each slide, parasitaemia will be 
determined independently by two readers and in the case of non-concordance an 
additional read by a third independent reader will be carried out. Since there will be no 
full blood count performed in the study subjects the used methodology for the 
determination of P. falciparum asexual parasite density may be based on an assumed 
white cell count of 8000/µL. Please refer to APPENDIX A for a description of other
methodologies for the determination of P. falciparum asexual parasite density. 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
43
14-SEP-2018
CCI

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
14-SEP-2018
44
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.
SAFETY
The procedure of capillary blood sampling will be performed once at the survey visit. 
Only SAEs related to the blood sampling procedure that occur in temporal association 
with the procedure will be recorded (up to 7 days after the survey visit).
The investigator or site staff is/are responsible during the study for the detection and 
documentation of events meeting the criteria and definition of a SAE as provided in this 
protocol. 
Each subject’s parent(s)/ LAR(s) will be instructed to contact the investigator 
immediately should the subject manifest any signs or symptoms they perceive as serious.
6.1.
Safety definitions
6.1.1.
Definition of a serious adverse event
An SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
NB: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
44
14-SEP-2018
CCI

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
45
c.
Requires hospitalisation or prolongation of an existing hospitalisation,
NB: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. 
Complications that occur during hospitalisation are also considered AEs. If a 
complication prolongs hospitalisation or fulfils any other serious criteria, the event 
will also be considered serious. When in doubt as to whether ‘hospitalisation’ 
occurred or was necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an SAE.
d.
Results in disability/incapacity, 
NB: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g., sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption.
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.
6.2.
Detecting and recording SAEs
6.2.1.
Time periods for detecting and recording SAEs
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) will be collected and recorded from the time the subject consents to participate 
in the study/study start until she/he is discharged from the study.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
45
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
46
6.2.2.
Evaluation of SAEs
6.2.2.1.
Active questioning to detect SAEs
When an 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 the SAE 
in the eCRF. The investigator is not allowed to send photocopies of the subject’s medical 
records to GSK Biologicals instead of appropriately completing the eCRF. However, 
there may be instances when copies of medical records for certain cases are requested by 
GSK Biologicals. In this instance, all subject identifiers will be blinded on the copies of 
the medical records prior to submission to GSK Biologicals.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/ or other clinical information. In such cases, the diagnosis should 
be documented as the SAE and not the individual signs/symptoms.
6.2.2.2.
Assessment of the intensity of SAEs
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all SAEs recorded during the study. The assessment will be based on the 
investigator’s clinical judgement.
The intensity should be assigned to one of the following categories:
1 (mild)
=
An SAE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2 (moderate)
=
An SAE which is sufficiently discomforting to interfere with 
normal everyday activities.
3 (severe)
=
An SAE which prevents normal, everyday activities
(in a young child, such an AE would, for example, prevent 
attendance at school/ kindergarten/ a day-care centre and would 
cause the parent(s)/ LAR(s) to seek medical advice.)
An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as 
described in Section 6.1.1.
6.2.2.3.
Assessment of causality
The investigator should assess the causality of each SAE. The investigator will use 
clinical judgement to determine the relationship between the SAEs and study 
participation. Alternative causes, such as natural history of the underlying diseases, other 
concomitant therapy and other risk factors will be considered and investigated.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
46
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
47
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. 
If an event meets the criteria to be considered as ‘serious’ (see Section 6.1.1), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possibly contributing factors to each SAE.
Possibly contributing factors include:

Medical history.

Concomitant medication.

Protocol required procedure.

Other procedure not required by the protocol.

Other cause (specify).
6.2.2.4.
Assessment of outcomes
The investigator will assess the outcome of all SAEs recorded during the study as:

Recovered/ resolved.

Recovering/ resolving.

Not recovered/ not resolved.

Recovered with sequelae/ resolved with sequelae.

Fatal.
6.3.
Reporting of SAEs
6.3.1.
Prompt reporting of SAEs related to study participation to GSK 
SAEs that occur in the time period defined in Section 6.2.1 will be reported promptly to 
GSK within the timeframes described in Table 6 once the investigator determines that the 
event meets the protocol definition of an SAE.
Table 6
Timeframes for submitting SAEs related to study participation to 
GSK 
Type of event
Initial reports
Follow-up of relevant information
on a previous report
Timeframe
Documents
Timeframe
Documents
SAEs related to study 
participation
24 hours*
Electronic SAE report
24 hours*
Electronic SAE report
* Timeframe allowed after receipt or awareness of the information.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
47
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
48
6.3.2.
Contact information for reporting SAEs to GSK 
Study Contact for Reporting SAEs 
Refer to the local study contact information document.
Back-up Study Contact for Reporting SAEs
24/24 hour and 7/7 day availability:
GSK Biologicals Clinical Safety & Pharmacovigilance
Email: RIX.CT-Safety-Vac@gsk.com
Fax: +32 2 656 51 16 or +32 2 656 80 09
6.3.3.
Completion and transmission of SAEs reports related to study 
participation to GSK
Once an investigator becomes aware that an SAE has occurred in a study subject, the 
investigator (or designee) must complete the information in the electronic Expedited 
Adverse Event Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding an SAE, the report should still be completed within 24 
hours. Once additional 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.
6.3.3.1.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or designee) must 
complete, then date and sign a paper Expedited Adverse Event 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 reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designee) must complete the electronic Expedited Adverse 
Event Report within 24 hours. The final valid information for regulatory reporting will be 
the information reported through the electronic reporting system. 
6.3.4.
Updating of SAE information after freezing of the subject’s eCRF
When additional SAE information is received after freezing of the subject’s eCRF, new 
or updated information should be recorded on a paper Expedited Adverse Event 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 (see the Sponsor Information) within the designated 
reporting time frames specified in Table 6.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
48
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
49
6.3.5.
Regulatory reporting requirements for SAEs
The investigator will promptly report all SAEs to GSK Biologicals in accordance with 
the procedures detailed in Section 6.3.1. 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 epidemiological 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.
6.4.
Follow-up of SAEs
6.4.1.
Follow-up during the study
After the initial SAE report, the investigator is required to proactively follow each subject 
and provide further relevant information on the subject’s condition to GSK Biologicals 
(within 24 hours for SAEs, refer to Table 6).
All SAEs documented at a previous visit/ contact and recorded as not recovered/ not 
resolved or recovering/ resolving will be reviewed at subsequent visits/ contacts until the 
end of the study.
6.4.1.1.
Follow-up after the subject is discharged from the study
The investigator will follow-up subjects:

With SAEs until the event has resolved, subsided, stabilised, disappeared, or until the 
event is otherwise explained, or the subject is lost to follow-up.
If the investigator receives additional relevant information on a previously reported SAE, 
he/ she will provide this information to GSK Biologicals using a paper Expedited 
Adverse Event Report.
GSK Biologicals may request that the investigator performs or arranges for the conduct 
of additional clinical examinations/ tests and/ or evaluations to elucidate as fully as 
possible the nature and/ or causality of the SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
49
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
50
7.
STATISTICAL METHODS
7.1.
Endpoints
7.1.1.
Primary endpoints
Primary

Occurrence of P. falciparum parasitaemia (using microscopy)
Criteria/definitions: infection with P. falciparum determined using a blood smear 
slide and determined using microscopy.

Occurrence of malaria control interventions
Criteria/definitions: malaria control interventions are mosquito net usage 
(including insecticide-treated nets [ITN] and long lasting insecticidal nets 
[LLIN]), indoor residual spraying (IRS), seasonal malaria chemoprevention 
(SMC), intermittent preventative treatment in infants (IPTi), and ACT therapy 
received within the last 14 days.
(Amended 14 September 2018)
7.1.2.
Secondary endpoints
Secondary

Demography and history characteristics
Criteria/definitions: gender, age, medical history.

Occurrence of Plasmodium species other than P. falciparum (using microscopy)
Criteria/definitions: infection with Plasmodium species other than P. falciparum
determined using a blood smear slide and microscopy.

Occurrence of uptake and timing of the third dose of DTP/HepB/Hib and the first 
measles EPI vaccines
Criteria/definitions: vaccination record of receipt of dose 3 of the DTP/HepB/Hib 
and the first dose of the measles EPI vaccines.

Occurrence of anti-malarial therapy
Criteria/definitions: any anti-malarial therapy received in the last 14 days.

Occurrence of measured fever
Criteria/definitions: any measured fever at time of visit (axillary temperature 
≥37.5°C).

Occurrence of reported fever
Criteria/definitions: any reported fever occurring in the last 24 hours.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
50
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
51

Occurrence of care seeking behaviour
Criteria/definitions: occurrence of visits to health providers following reported fever 
or malaria in the previous 14 days.

Geo-referencing characteristics
Criteria/definitions: positioning of the subject’s residence will be attributed to a 
segment with a unique ID from the grid referencing study area map in which the 
subject resides, where necessary, grouping small geographically proximate villages 
so that each segment has at least 10 study subjects to avoid PII, and proceeding as far 
as geographically appropriate.

Occurrence of individual malaria prevention measures and risk factors
Criteria/definitions: malaria prevention measures are repellents and local herbs not 
specifically recommended by the national programme and risk factors are rural/urban 
area, construction material for the house, floor and roof, type of eaves (open/closed), 
use of electricity and water source (distance from and type).
7.1.3.
Tertiary endpoints

Occurrence of RTS,S/AS01E vaccine doses
Criteria/definitions: vaccination record of each dose received of the RTS,S/AS01E
vaccine..

Occurrence of P. falciparum parasitaemia (using NAAT)
Criteria/definitions: detection of P. falciparum on dried blood spot and determined 
using NAAT.

Occurrence of sexual P. falciparum parasitaemia (using microscopy)
Criteria/definitions: detection of sexual P. falciparum using a blood smear slide and 
determined using microscopy.

Occurrence of sexual P. falciparum (using NAAT/QT-NASBA)
Criteria/definitions: detection of sexual P. falciparum on dried blood spot and 
determined using NAAT.
7.2.
Determination of sample size
In this study, sample sizes have been designed to ensure sufficiently narrow confidence 
intervals (CIs) around centre-wise parasite prevalence estimates (with a maximum 
residual standard error [RSE] of 0.25) according to the WHO definition [WHO, 1963] (2-
9 years) and to the JTEG requested age (<5 years).
Moreover, when these estimates are used to adjust vaccine clinical malaria estimates 
from EPI-MAL-002/-003 for annual fluctuations in MTI and control measure use, a 
sufficient level of precision for the vaccine ineligible subgroup is maintained. In addition, 
the ability to detect longitudinal trends in parasite prevalence has been considered in 
these sample size calculations.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
51
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
52
7.2.1.
Children aged 6 months to <5 years
The sample size is computed for each centre separately and is considered for the point 
estimate of prevalence of infection among children aged at least 6 months and less than 5
years during one cross-sectional survey. 
The effective sample size is computed to obtain an estimation of the prevalence of 
infection with a relative standard error equal to a maximum of 0.25. 
Given that the expected sample size should be greater than 100, CI limits are computed 
using the approximated 95% CI. 
In Table 7 values of the CI limits are computed for several expected parasite prevalences
in function of effective sample sizes equal to 100, 200, 300, 400, 600 and 1000 subjects. 
To meet the criteria of precision defined above, the effective sample sizes are 400 eligible 
subjects. Indeed, for an expected parasite prevalence of 5%, the RSE is equal to 0.23 
(= half-width of CI / 2*p) (shaded values in Table 7).
Table 7
Approximated 95% CI limits around different values of observed 
parasite prevalence computed in function of several sample sizes
In Figure 1, precision around expected parasite prevalence is illustrated taking into 
account the defined sample size. For example, for an expected parasite prevalence of 7%, 
the lower and upper limits of the approximated 95% CI are equal to 4.8% and 10.1%, 
respectively. For an expected parasite prevalence of 31%, the limits are 25.9% and 
36.6%, respectively.
5
10
20
25
30
40
50
60
70
80
90
LL (%)
1.9
5.2
12.9
17.1
21.5
30.5
39.9
49.7
59.9
70.6
82.0
UL (%)
11.8
18.0
29.4
34.8
40.1
50.3
60.1
69.5
78.5
87.1
94.8
LL (%)
2.6
6.4
14.8
19.3
23.8
33.2
42.9
52.8
63.1
73.6
84.8
UL (%)
9.3
15.2
26.4
31.7
36.9
47.2
57.1
66.8
76.2
85.2
93.6
LL (%)
2.9
7.0
15.7
20.3
24.9
34.5
44.2
54.2
64.4
74.9
85.9
UL (%)
8.3
14.1
25.1
30.4
35.6
45.8
55.8
65.5
75.1
84.3
93.0
LL (%)
3.2
7.3
16.3
20.9
25.6
35.2
45.0
55.0
65.2
75.7
86.5
UL (%)
7.7
13.5
24.3
29.6
34.8
45.0
55.0
64.8
74.4
83.7
92.7
LL (%)
3.5
7.8
16.9
21.6
26.4
36.1
45.9
55.9
66.1
76.5
87.2
UL (%)
7.1
12.8
23.5
28.7
33.9
44.1
54.1
63.9
73.6
83.1
92.2
LL (%)
3.8
8.2
17.6
22.4
27.2
37.0
46.9
56.9
67.0
77.4
87.9
UL (%)
6.6
12.1
22.6
27.8
33.0
43.1
53.1
63.0
72.8
82.4
91.8
1000
Expected parasite prevalence
200
300
400
600
Sample size
Approx. 95% CI
100
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
52
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
53
Figure 1
Illustration of the lower (LL) and upper (UL) limits of the 
approximated 95%CI built around observed parasite prevalences for 
a sample of 400 subjects
Study sites are in different endemicity classes, so a sample of 400 subjects in this age 
class will allow for suitable confidence limits around parasite prevalence estimates for 
sites within each of the endemicity classes.
(Amended 14 September 2018)
Note that with the sampling strategy using the proposed stratification by age 
(Section 4.1.2), 400 eligible subjects aged at least 6 months and less than 5 years will be 
recruited. 
7.2.2.
Children aged 2 to <10 years 
Based on the defined recruitment scheme (see Section 4.1.1), the sample size of children 
aged 2 to <10 years will be approximately equal to the number of eligible subjects aged 
0-5 years; ensuring the adequate precision for this age group. Indeed, following the 
recruitment scheme explained in Section 4.1.1, 420 subjects would be aged between 2 to 
<10 years.
7.2.3.
Children aged 5 to <10 years
Concerning children aged at least 5 years and less than 10 years, the effective sample size 
is computed to obtain an estimation of the prevalence of infection with a relative standard 
error equal to a maximum of 0.35. Therefore, the sample size will be approximately 200 
eligible subjects (see Figure 2). 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
53
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
54
Figure 2
Illustration of the lower (LL) and upper (UL) limits of the 
approximated 95%CI built around observed parasite prevalences for 
a sample of 200 subjects
Since the precision of 0.25 was adequate and determined for the WHO (children aged 6 
months to <5 years) and JTEG (children aged 2 to <10 years) definitions, the sample size 
for the subgroup of children 5-9 years was fixed at 200 which gives a relative standard 
error equal to a maximum of 0.35. In addition, it is anticipated that children in this older 
age group are more likely to be at school and it may take longer to recruit this age group 
with subsequent logistics and financial implications.
7.3.
Cohorts for Analyses
7.3.1.
Total cohort
The Total cohort will include all subjects enrolled in the study. 
All the information for these subjects will be collected in the eCRF (after receiving 
signed informed consent).
7.3.2.
According-To-Protocol cohort
The According to Protocol (ATP) cohort will include all evaluable subjects (i.e. those 
meeting all eligibility criteria, complying with the procedures defined in the protocol, 
with no elimination criteria during the study) for whom at least one laboratory result of 
the blood sample is available.
A detailed, comprehensive list of reasons for elimination from ATP analyses will be 
established at the time of data cleaning.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
54
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
55
7.4.
Derived and transformed data

Age in the study will be computed as the difference between the date of informed 
consent and the date of birth. The age will be expressed in the following groups: 0.5
to <3 years, 3 to <5 years, 5 to <10 years. 

The fever status will be derived from the axillary temperature measured at the time 
of the visit. The value ‘Yes’ will be given if the temperature is 37.5°C.

The parasite density will be grouped into the following classes:

Low: <2500 parasites/ μL

Medium: 2500 – 9999 parasites/ μL

High: 10000 – 19999 parasites/ μL

Very high: ≥20000 parasites/ μL
In the case of two positive slides readings, the parasites density (parasites/μL) at the 
subject level will be defined as the geometric mean of both (those positive) slide 
reading values if the subject status is defined as positive. In the case of three positive 
slide readings, the two closest readings will be selected to calculate the geometric 
mean. In the case of negative parasite status, the density will be recorded as missing. 
7.5.
Analysis of demographics
The number of subjects enrolled as well as the number excluded from the ATP analyses 
will be presented. Demographic characteristics (age and gender) will be summarised 
using descriptive statistics. 
Centre specific data regarding the malaria control programme will be summarised for 
each site and cross-surveys separately.
7.6.
Analysis of primary objectives
The parasite prevalence will be estimated as the proportion of subjects infected divided 
by the number of subjects tested. All CIs will be two-sided 95% CIs computed using the 
exact method, calculated from Proc StatXact [Clopper, 1934]. The estimates of parasite 
prevalence will be done each year and for each site separately.
The estimates of the use of malaria control measures will be estimated the same way; as 
the proportions of subjects using malaria control measures divided by the number of 
subjects for which this information is available.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
55
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
56
7.7.
Analysis of secondary objectives
7.7.1.
Trends in parasite prevalence
7.7.1.1.
Overall
First the trends in parasite prevalence between each cross-sectional malariometric surveys 
will be tested using the Cochran-Armitage trend test [Agresti, 1990]. This hypothesis test 
will be performed on the parasite prevalence computed on the independent samples of 
subjects in each survey separately within each site.
7.7.1.2.
By vaccine eligible/ineligible subgroup: Statistical analyses for vaccine 
association adjustments and association between vaccine and 
transmission
For the analysis of association between RTS,S/AS01E vaccine and transmission, two 
subgroups must be considered: 

Vaccine eligible subgroup (see glossary of terms for definition). This subgroup will 
be used to assess the association between vaccination and transmission intensity, 
assuming a constant MTI in unvaccinated subjects (which will be measured using the 
second subgroup).

Vaccine ineligible subgroup (see glossary of terms for definition). Due to the fact 
that the main reservoir of malaria is in the population between 5-20 years old (based 
on data collected in parallel [Epi-Mal-001 study] to the pivotal efficacy Phase III
trial, not published) and MTI will be assessed for approximately 5 years following 
the introduction of the vaccine, it will be assumed that there will be negligible herd 
immunity effect. Therefore, this subgroup will be used to detect any annual 
fluctuation (control group). If there is any herd effect, then the vaccine effect will be 
an underestimate.
(Amended 14 September 2018)
7.7.1.2.1.
Annual fluctuations: vaccine ineligible subgroup
Once the cross-surveys are collected, the independent samples of subjects in each survey 
will be tested and assessed using a Chi-square statistic to test the significance of the 
differences among the parasite prevalences in each survey; meaning annual fluctuations.
If a significant difference is detected, further analyses will be done to characterise the 
difference(s).
Two methods will be then used. The first method is by two-by-two comparison between 
each cross-survey result. The advantage is identification of non-linear variations. The 
disadvantage is that longitudinal aspects of all surveys are not taken into consideration. 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
56
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
57
As shown in Table 8 and in Figure 3, a relative risk (RR) of one year of the study to 
another equal to 0.8 and 0.6 could be detected for a baseline prevalence greater than 60% 
and 20%, respectively. Note; these statements are based on non-overlapping CIs. 
Table 8
Power estimation to detect a certain RR (from 0.1 to 0.9) depending 
on different baseline prevalences (from 0.1 to 0.9) with a sample size 
of 360 subjects
Figure 3
Illustration of the lower (LL) and upper (UL) limits of the exact 95%
CI built around both compared prevalences with a sample size of 
360 subjects
a.
based on a RR of 0.8
Baseline
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0.1
1
1
0.97
0.89
0.72
0.51
0.3
0.15
0.07
0.2
1
1
1
1
0.97
0.83
0.57
0.29
0.1
0.3
1
1
1
1
1
0.97
0.79
0.44
0.14
0.4
1
1
1
1
1
1
0.93
0.61
0.2
0.5
1
1
1
1
1
1
0.98
0.77
0.27
0.6
1
1
1
1
1
1
1
0.9
0.37
0.7
1
1
1
1
1
1
1
0.97
0.51
0.8
1
1
1
1
1
1
1
1
0.71
0.9
1
1
1
1
1
1
1
1
0.93
Relative Risk
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
57
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
58
b.
based on a RR of 0.6
The second method is to perform a Cochran linear hypothesis trend test in which all 
longitudinal estimations will be used to detect a linear trend. However, only linear trends 
could be detected. As shown in Figure 4, a 5% decrease could not be detected if the 
baseline incidence is smaller than 50%. Based on 4 surveys, and a threshold of 90% 
power, a 10% decrease could be detected for a baseline incidence higher than or equal to 
40% and a 15% decrease could be detected for a baseline incidence higher than or equal 
to~25%. The power improves with an increased number of surveys.
Table 9
Power estimation to detect a certain RR (from 0.1 to 0.9) depending 
on different baseline prevalence with a sample size of 240 subjects
Baseline
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0.1
0.99
0.96
0.88
0.73
0.55
0.36
0.22
0.12
0.06
0.2
1
1
1
0.97
0.87
0.67
0.42
0.21
0.08
0.3
1
1
1
1
0.98
0.87
0.62
0.32
0.11
0.4
1
1
1
1
1
0.97
0.79
0.45
0.14
0.5
1
1
1
1
1
0.99
0.92
0.6
0.19
0.6
1
1
1
1
1
1
0.98
0.75
0.26
0.7
1
1
1
1
1
1
1
0.89
0.37
0.8
1
1
1
1
1
1
1
0.98
0.54
0.9
1
1
1
1
1
1
1
1
0.8
Relative Risk
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
58
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
59
Figure 4
Illustration of the power to detect a trend using the Cochran trend 
test, and based on a sample size of 360 subjects and an assumed 
decrease each year of 5%, 10% or 15%
7.7.1.2.2.
Association between vaccine and parasite prevalence: vaccine eligible 
subgroup
Using the same first methodology for the vaccine ineligible subgroup (Section 7.7.1.2.1), 
a statistically significant difference could be detected for a RR of 0.8 and 0.6 at a baseline 
prevalence greater than 70% and 30%, respectively, as shown in Figure 5 or in Table 9.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
59
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
60
Figure 5
Illustration of the lower (LL) and upper (UL) limits of the exact 95%
CI built around both compared prevalences with a sample size of 
240 subjects
a.
based on a RR of 0.8
b.
based on a RR of 0.6
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
60
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
61
7.7.2.
Other prevalences and proportions
The parasite prevalence and the estimates of the use of malaria control measures will be 
estimated by age group as defined in Section 7.4. 
The prevalence of Plasmodium species other than P. falciparum will be estimated as the 
proportion of subjects infected divided by the number of subjects tested.
Prevalence for each segment will be estimated using the following criteria for level of 
endemicity: ‘high’ ≥ 60%, ‘moderate’ 20%-59%, and ‘low’ <20% relating to the 
proportion of infected children in each segment [Snow, 1997; Omumbo, 1998]. 
The proportion of subjects having received the third dose of DTP/HepB/Hib and the first 
dose of measles EPI vaccine will be estimated as the ratio of the subjects having received 
the third dose of DTP/HepB/Hib and the first dose of measles EPI vaccine divided by the 
number of subjects who should have received the third dose of DTP/pentavalent and the 
first dose of measles EPI (i.e. 14 weeks and 9 months of age, respectively). Moreover, 
among the subjects having received the third dose of DTP/HepB/Hib and the first dose of
measles EPI vaccine, the proportions of subjects having received them on time, in 
advance and with delay will be estimated.
The care seeking behaviours will be described as the proportions of subjects having 
received care among all subjects with reported fever or malaria in the previous 14 days
by the place they sought for care.  
The prevalence of gametocyte presence will be estimated as the proportion of subjects 
infected divided by the number of subjects tested.
The parasite and gametocyte prevalences will also be estimated separately for 
microscopy and NAAT results.
7.7.3.
Within-site geographical heterogeneity and risk factors
To assess within-site geographical heterogeneity, the parasite prevalence will be 
estimated separately in each village, grouping villages where necessary. Moreover, these 
geo-referencing characteristics will be part of the risk factor analysis described hereafter.
To describe the risk factors for malaria, a multivariable logistic regression will be used 
with all potential confounding variables.
7.8.
Analysis of tertiary objectives
The comparisons of asexual and sexual (gametocyte) parasitaemia measured by 
microscopy and NAAT will be done using Cohen’s Kappa coefficient. The hypothesis 
test will be done per centre, and overall.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
61
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
62
7.9.
Interpretation of analyses
Comparative analyses will be descriptive with the aim to characterise the difference 
between groups in the endpoint(s) related to the objective(s). These descriptive analyses 
should not be interpreted.
7.10.
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.
7.10.1.
Sequence of analyses
The analysis will be performed in each epoch, on as clean as possible data for the initial 
epochs and on clean data for the final epoch. The objective assessing trends will be 
analysed only at the final epoch. The other objectives will be analysed at all epochs. 
All analyses, apart from the trend analyses, will be done for each epoch by centre and by 
classes of age (6 months to <5 years versus 5 to <10 years and 6 months to <3 years 
versus 3 to <10 years), and by year for the age group 6 months to <5 years. They will be 
detailed in the Statistical Analysis Plan (SAP) and the Tables, Figures, Listings (TFL)
before the analysis. Statistical reports will be written after each epoch. A clinical report 
will be written after Surveys 2 and 5 and an integrated report will be written at the end of 
the study.
7.10.2.
Statistical considerations for interim analyses
Only descriptive analyses and estimations of point estimate prevalence will be computed 
for each interim analysis. These analyses will be descriptive only. Therefore no 
adjustment of type I error is needed. 
Concerning the sample size required for each interim analysis, please refer to Section 7.2. 
8.
ADMINISTRATIVE MATTERS
To comply with ICH GCP or other applicable guidelines administrative obligations 
relating to data collection, monitoring, archiving data, audits, confidentiality, ownership 
and publications must be met.
8.1.
Electronic Case Report Form instructions
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
62
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
63
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
Once the database is archived and the clinical study report is complete and approved by 
all parties, each participating investigator will be provided with a CD-ROM of the final 
version of the data generated at his/her investigational site.
8.2.
Study monitoring by GSK Biologicals
GSK will monitor the study to verify that, amongst others, the: 

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform 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. 
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.
For eCRF, the monitor will mark completed and approved screens at each visit. 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with
applicable regulations, GCP, and GSK procedures.
8.3.
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 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
63
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
64
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. 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 or other applicable 
guidelines, any institutional requirements or applicable laws or regulations, or GSK 
standards/procedures; otherwise, the minimum retention period will default to 15 years. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility and transfer of 
ownership of the records in the event the investigator leaves the site.
8.4.
Quality assurance
To ensure compliance with GCP or other applicable guidelines and all applicable 
regulatory requirements, GSK may conduct a quality assurance audit. Regulatory 
agencies may also conduct a regulatory inspection of this study. Such audits/inspections 
can occur at any time during or after completion of the study. If an audit or inspection 
occurs, the investigator and institution agree to allow the auditor/inspector direct access 
to all relevant documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues.
8.5.
Posting of information on publicly available registers and 
publication policy
Study information from this protocol will be posted on public registers before enrolment 
of subjects begins.
Interventional studies that do not evaluate vaccines/products are progressed for 
publication in the scientific literature when the results provide important scientific or 
medical knowledge.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
64
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
65
8.6.
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 Biologicals site or other 
mutually-agreed 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.
9.
COUNTRY SPECIFIC REQUIREMENTS
Not applicable.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
65
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
66
10.
REFERENCES
Agresti A. Categorical Data Analysis. New York: John Wiley & Sons, Inc; 1990.
Clopper CJ and Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of binomial. Biometrika 1934; 26:404-413.
International Society for Pharmacoepidemiology (ISPE). Guidelines for Good 
Pharmacoepidemiology Practices (GPP). Rev 3 (June 2015). 
http://www.pharmacoepi.org/resources/guidelines_08027.cfm; 2015. Accessed 14 June 
2017.
Omumbo J, Ouma J, Rapuoda B et al. Mapping malaria transmission intensity using 
geographical information systems (GIS): an example from Kenya. Ann Trop Med 
Parasitol 1998;92(1):7-21. Erratum in: Ann Trop Med Parasitol 1998;92(3):351. 
Roll Back Malaria Monitoring and Evaluation Reference Group, World Health 
Organization, United Nations Children’s Fund, MEASURE DHS, MEASURE 
Evaluation, and U.S. Centers for Disease Control and Prevention. 2005. Malaria Indicator 
Survey: Basic documentation for survey design and implementation. Calverton, 
Maryland: MEASURE Evaluation.
Snow RW, Omumbo JA, Lowe B, et al. Relation between severe malaria morbidity in 
children and level of Plasmodium falciparum transmission in Africa. Lancet
1997;349(9066):1650-4.
World Health Organization. Terminology of malaria and of malaria eradication: report of 
a drafting committee. 1963. WHO, Geneva.
http://whqlibdoc.who.int/publications/9241540141.pdf.
World Health Organization. Basic Malaria Microscopy Part I: Learner’s Guide (1991). 
WHO, Geneva. http://whqlibdoc.who.int/publications/1991/9241544309.pdf.
World Health Organization. WHO malaria quality assurance manual version 1 (2009): 
WHO. 
Geneva.http://www.who.int/malaria/publications/malaria_microscopy_QA_manual.pdf.
World Health Organisation. Malaria. Fact sheet No 94. Reviewed March 2013. 
http://www.who.int/mediacentre/factsheets/fs094/en/index.html.
(Amended 14 September 2018)
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
66
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
67
APPENDIX A
LABORATORY ASSAYS - DETERMINATION OF 
PARASITAEMIA BY MICROSCOPY
Slide reading methodology
All slide readers will be required to demonstrate proficiency at “Competent” level or 
above as documented by certification/training records [World Health Organization, 
2009]. 
For further details of the reading methodology described, refer to the WHO Basic Malaria 
Microscopy Learners Guide [World Health Organization, 1991].
Slide preparation and assessing parasite presence
Slide preparation: During subject visits, capillary blood samples are used to produce 
two slides per subject containing both a thick and thin blood smear per slide. The thin 
film is produced from one small blood drop in the centre of the slide. Using the edge of a 
second, clean slide, firmly spread the single drop of blood across the sample slide. The 
thick film is produced from 3 larger drops of blood approximately 1cm away from the 
thin film. The drops should be joined and spread using the corner of the spreader to 
become a circular thick film of approximately 1cm diameter.
Thick film examination: A 100-field examination of the thick film should be conducted 
to assess presence of parasites and species. 
Negative result: 100 fields free of parasites are read before a slide is declared negative.
Positive result: If parasites are present within reading of 100 fields, the slide is positive. 
Positive slides are examined for a further 100 fields to ensure all species present are 
detected. 
Parasite density counting against assumed 8000 leukocytes per microlitre
In this method of estimating parasite density, it is assumed that there are 8000 leukocytes 
per microlitre of blood.
Step 1: Use 2 tally counters, one to count parasites and the other to count leukocytes. 
a.
If upon counting 200 leukocytes, 10 or more parasites have been counted, the results 
can be recorded as the parasites per 200 leukocytes.
b.
If upon counting 200 leukocytes, 9 or fewer parasites have been recorded, the reader 
should continue counting until 500 leukocytes have been counted and the number of 
parasites per 500 leukocytes can be recorded.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
67
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
68
Step 2: Convert the number of parasites relative to leukocyte count to an estimated 
number of parasites per microlitre:
number of parasites x 8000
= parasites per microlitre
number of leukocytes
For example, if 20 parasites were observed upon counting 500 leukocytes, it would give 
an estimated 320 parasites per microlitre.
It should be noted that the count should be by species, and counts for P. falciparum
should be made for both gametocytes and asexual parasites.
Criteria for concordance for double reading of slides
All slides will be read twice, by two independent readers to quantify the P. falciparum
parasite presence and density. If slides are judged to be discordant, a third independent 
read will be organised in the following cases:

The result from one reader is negative and the one of the other is positive.

For high and medium positive parasitaemia results (blood parasitaemia >400/L), 
the higher count divided by the lower count is >2.

For low parasitaemia (blood parasitaemia 400/L), the highest reading density is 
more than one log10 higher than the lowest reading.

If parasitaemia result is high or medium in one slide and the result from the other 
slide reading is low, i.e. one is >400/L and the other is 400/L, criterion (C) will 
be applied.
Determination of final result
If there are two concordant results the final result is the geometric mean of the two 
readings.
If the first two readings are discordant then the final result will follow the following 
principles: 

For cases of positive/negative discrepancy (A), the majority decision will be adopted. 
If the decision is positive, the final result will be the geometrical mean of the two 
positives.

For cases of three positive reads (B and C), the final result will be the geometric 
mean of the two geometrically closest readings.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
68
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
69
Identification of Plasmodium species
Positive parasitaemia identified on any thick blood film must always be identified to 
species. This will be done on thin blood film except in case of low parasitaemia. 
Archiving of blood slides
Two blood slides are taken, one for reading and archiving at the centres; the second one 
will be archived centrally at a GSK dedicated laboratory facility.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
69
14-SEP-2018
CCI

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
70
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
70
14-SEP-2018
CCI

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
71
APPENDIX B
CLINICAL LABORATORIES
Table 10
Outsourced laboratories
Laboratory
Address
Academic Medical Center (AMC)
Laboratory for clinical parasitology, L1-247 
Department of Medical Microbiology
Meibergdreef 9 
1105 AZ Amsterdam
The Netherlands
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
71
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
72
APPENDIX C
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals
Vaccine Value & Health Science (VVHS)
Protocol Amendment 1
eTrack study number 
and Abbreviated Title
116682 (EPI-MALARIA-005 BOD AME)
Amendment number:
Amendment 1
Amendment date:
21 September 2016
Co-ordinating author:
, XPE Pharma & Sciences for GSK 
Biologicals
1.
Risk Management Plan requirement for follow-up extension in EPI-MAL-003 
study. EPI-MAL-005 study is conducted in parallel with the EPI-MAL-002 and 
EPI-MAL-003 studies, and therefore with the extension of EPI-MAL-003, there is 
need to extend the EPI-MAL-005 study which provides useful data to compare the 
EPI-MAL-002 and EPI-MAL-003 studies. EPI-MAL-005 study has been extended 
by four years to nine years.
2.
New sites selected for the EPI-MAL-002 and EPI-MAL-003 studies will be 
included in this study. In addition, World Health Organisation (WHO) proposed 
the use of RTS,S/AS01E in moderate to high malaria transmission settings. Due to 
WHO’s proposal, the two sites in Senegal and one site in Tanzania will no longer 
be participating in this study after Survey 2 because the malaria transmission in 
these countries is low. 
3.
The study design was updated to indicate that there is an overlap of EPI-MAL-002 
and EPI-MAL-003 with no break.
4.
The word “interventional” was removed from the detailed title of the study 
because this word is no longer in the detailed title of EPI-MAL-002.
5.
The tertiary objectives wording has been updated. P. falciparum gametocyte 
NASBA assay was initially expected to be semi-quantitative, but during the 
method optimisation the assay was more variable than expected. Therefore the test 
will only be considered as qualitative.
6.
The name and address of the laboratory where the NAAT tests will be performed 
were updated because the activities and projects of laboratory have been 
transferred to the Academic Medical Centre in Amsterdam.
7.
The sample size wording has been updated to reflect the true reason for the limited 
sample size in children 5-9 years to reach a relative standard error equal to a 
maximum of 0.35 based on the Pharmacovigilance Risk Assessment Committee 
(PRAC)‘s recommendation.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
72
14-SEP-2018
PPD

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
73
8.
The quantity of blood needed for asexual and sexual (gametocyte) assessment and 
parasite and gametocyte NAAT assessment has been updated. 
9.
The criteria for when the rapid diagnostic test will be done has been updated from 
not only for fever > 37.5C, but also for subjects with other symptoms/signs of 
clinical malaria.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Detailed Title 
An epidemiology study to assess Plasmodium falciparum
parasite prevalence and malaria control measures in 
catchment areas of two interventional studies pre- and post 
RTS,S/AS01E introduction (EPI-MAL-002 and EPI-MAL-
003) to assess, in field conditions, vaccine benefit:risk in 
children in sub-Saharan Africa.
Co-ordinating author
, Freelance Science Writer for GSK 
Biologicals
Contributing authors 

, Project Statistician Lead 
Epidemiologist-Malaria

, Oversight Data Manager, Business 
and Decision Life Sciences for GSK Biologicals

Study Data Manager

, Clinical Laboratory Sciences-
SM, external consultant for GSK Biologicals 

, Study Delivery Lead, 
SynteractHCR Benelux NV for GSK Biologicals

, Study Statistician, 4clinics for GSK 
Biologicals 

, Senior Manager, Epidemiologist,
ManiAfriCare for GSK Biologicals

, WHO Fellow, Malaria Team
Clinical Epidemiologist, Bartech for GSK Biologicals

, Senior Local Delivery Lead

, Global Patent representative
Copyright 2014-2016 of the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
73
14-SEP-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
74
Protocol Amendment 1 Sponsor Signatory Approval
Detailed Title 
An epidemiology study to assess Plasmodium 
falciparum parasite prevalence and malaria control 
measures in catchment areas of two interventional
studies pre- and post RTS,S/AS01E introduction 
(EPI-MAL-002 and EPI-MAL-003) to assess, in field 
conditions, vaccine benefit:risk in children in 
sub-Saharan Africa. 
Sponsor signatory
Laurence Baril, Head, Global Epidemiology
François Roman, Clinical & Epidemiology Project 
Lead, DDW Vaccines 
SYNOPSIS
Detailed Title
An epidemiology study to assess Plasmodium falciparum
parasite prevalence and malaria control measures in catchment 
areas of two interventional studies pre- and post RTS,S/AS01E
introduction (EPI-MAL-002 and EPI-MAL-003) to assess, in 
field conditions, vaccine benefit:risk in children in 
sub-Saharan Africa.
Rationale for the 
study 
Following the pivotal Phase III study of the candidate malaria 
vaccine RTS,S/AS01E (Malaria-055), two consecutive vaccine 
safety monitoring studies (EPI-MAL-002 and EPI-MAL-003) 
will be conducted to monitor incidence rates of meningitis,
protocol defined adverse events of specific interest (AESI),
and non-communicable and non-traumatic serious of other
adverse events (NC/NT-SAE).leading to hospitalisation or 
death, in children. The first study, EPI-MAL-002, is a 
surveillance study prior to RTS,S/AS01E authorisation in the 
country; the second study, EPI-MAL-003, will more 
specifically monitor RTS,S/ AS01E safety and will only start 
when RTS,S/AS01E is registered and authorised in the 
country. The planned age range for licensure of World Health 
Organization’s Strategic Advisory Group of Experts (SAGE) 
on Immunization and the Malaria Policy Advisory 
Committee (MPAC) recommended pilot implementations of 
RTS,S/AS01E candidate in children of 5–17 months of age, 
in parts of 3-5 sub-Saharan African (SSA) countries, 
administering 3 doses of the vaccine is in to children from 6 
weeks aged 5-9 months of age to less than18 months.in areas 
of moderate-to-high transmission of malaria with a fourth 
dose 15-18 months later. The first vaccine introduction is 
foreseen in 2018. The secondary endpoints of these studies 
also include monitoring the incidence of malaria disease as 
diagnosed during out-patient visits or hospitalisation. Up to 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
74
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
75
seven Health and Demographic Surveillance System (DSS
HDSS) (or equivalent system) sites in five countries in 
Sub-Saharan Africa will participate in these studies, enrolling 
approximately 4030 000 children <35 years of age in each 
study EPI-MAL-002 and approximately 45 000 children <5 
years in EPI-MAL-003.
This epidemiology study (EPI-MAL-005) is planned to run in 
parallel with these two studies, enrolling from the same DSS
HDSS or (equivalent system) populations.
Although not yet considered as the global gold standard, 
NAAT-based (nucleic acid amplification test) techniques can 
detect infections of lower malaria parasite density and give 
more accurate quantification of parasitaemia than is 
achievable by microscopy. Identification of gametocytes by 
microscopy is inherently challenging, thus their presence is 
often missed, even by highly trained technicians. Therefore, 
additional analysis of collected blood samples by NAAT will 
allow for the detection of lower density parasite infections and 
will be a more sensitive measure of changes in both parasite 
and gametocyte prevalence and density, thereby providing 
greater insight into potential changes upon vaccine 
implementation.
Objectives
Secondary

To estimate longitudinal trends in receipt and timing of 
the third dose of DTP/HepB/Hib pentavalent and the first 
dose of measles EPI vaccines, at around 14 weeks and 9 
months of age respectively, as appropriate by country.
Tertiary

To compare asexual and sexual (gametocyte) 
parasitaemia (qualitative- and semi-quantitative-density) 
when measured by microscopy or NAAT.
Study design

Biological samples: A capillary blood sample will be 
obtained for evaluation of malaria infection by blood 
slide and NAAT. In the event of measured fever at the 
time of the visit (axillary temperature ≥37.5°C) or fever 
reported in the last 24 hours or other symptoms/signs of 
clinical malaria, a rapid diagnostic test (RDT) will be 
conducted. If the RDT is positive, treatment will be given 
according to National guidelines. If a subject for whom 
no RDT was required is identified as being parasite 
positive following microscopy, National guidelines 
should be followed for clinical management of the 
subject.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
75
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
76

Each study site will be requested annually to provide 
centre specific information about interventions from the 
malaria control programme in the study area and, if 
facilities are available, to provide meteorological data for 
the study site such as rainfall and temperature. The 
information will be collected in the form of a 
questionnaire that will be recorded in a separate database 
to that for subject-specific data.

This study will involve up to 59 annual cross sectional 
surveys during malaria peak transmission.

Duration of the study: up to 59 years

NOTE: surveys may not be in consecutive years and 
the total will then be less than 5.

Epoch 006: Survey 6 at Year 6.

Epoch 007: Survey 7 at Year 7.

Epoch 008: Survey 8 at Year 8.

Epoch 009: Survey 9 at Year 9
Synopsis Table 1
Study groups and epochs foreseen in the study 
Study 
Group
Age 
(Min/
Max)
No 
of 
site
s
Total 
no of 
subject
s
Total no of 
subjects/sit
e
Epochs
Epoch 
001 
Survey 
1
Epoch 
002 
Survey 
2
Epoch 
003 
Survey 
3
Epoch 
004 
Survey 
4
Epoch 
005 
Survey 
5
Epoch 
006 
Survey 
6 
Epoch 
007 
Survey 
7 
Epoch 
008 
Survey 
8 
Epoch 
009 
Survey 
9 
Total
Study 
site
6 
month
s / 9 
years 
7
2100
3000
420060
0 
subject
s
4200
600 
subject
s
420060
0 
subject
s
4200
600 
subject
s
420060
0 
subject
s
600 
subject
s
600 
subject
s
600 
subject
s
600 
subject
s
Discussion of 
study design
Nine Up to 5 annual cross sectional surveys at peak transmission 
will provide point estimates of parasite prevalence and 
subsequently a longitudinal assessment of the level of 
endemicity in each area covered by EPI-MAL-002 and EPI-
MAL-003. Malaria transmission is highly seasonal so surveys 
will be carried out at the end during the course of the rainy 
season preferably when rains decrease, the period of highest 
malaria transmission.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
76
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
77
Number of 
subjects
Total expected sample size: 14000 subjects aged 6 months to <5 
years and 7000 subjects aged 5 to <10 years. Per site and by 
survey is a maximum of 400 subjects aged 6 months to <5 years 
and a maximum of 200 subjects aged 5 to <10 years. 
Endpoints
Secondary 

Occurrence of uptake and timing of the third dose of 
DTP/HepB/Hib pentavalent and the first measles EPI 
vaccines
Criteria/definitions: vaccination record of receipt of dose 3 of the 
DTP/HepB/Hib pentavalent and the first dose measles EPI 
vaccines.
LIST OF ABBREVIATIONS
AMC
Academic Medical Center
eCRF
Electronic case report form electronic Case Report Form
GCP
Good clinical practice Clinical Practice
GIS
Geographic Information System
HDSS
Health and Demographic surveillance system
HepB
Hepatitis B
Hib
Heamophilus influenza type b
KIT
Koninklijk Instituut voor de Tropen (Royal Tropical Institute)
MPAC
Malaria Policy Advisory Committee
PRAC
Pharmacovigilance Risk Assessment Committee
SAGE
Strategic Advisory Group of Experts
WHO
World Health Organisation
GLOSSARY OF TERMS
Catchment area:
In this study, the catchment area is defined as the area of 
the HDSS (or equivalent system) study site participating 
in the EPI-MAL-002 and EPI-MAL-003 studies.
DTP/HepB/Hib
This refers to DTP, or DTP-Hep B (tetravalent) or DTP-
HepB-Hib (pentavalent).
First dose measles
First measles containing vaccine.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
77
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
78
1
INTRODUCTION
1.1
Background
GSK Biologicals has formulated the candidate pre-erythrocytic P. falciparum malaria 
vaccine, RTS,S/AS01E, which is currently under evaluation. The vaccine consists of 
sequences of the circumsporozoite (CS) protein and hepatitis B surface antigen (HBsAg) 
adjuvanted with AS01 (liposome formulation with MPL and QS21 immunostimulants). 
In the pivotal Phase III study (Malaria-055), efficacy of the candidate malaria vaccine 
RTS,S/AS01E against first or only episodes of clinical malaria over a follow-up of 12 
months in children aged 5-17 months was 55.8% (p<0.0001), and in coadministration 
with DTPwHepB/Hib vaccine at 6, 10 and 14 weeks of age was 31.3% (p<0.0001).
1.2
Rationale for the study
Following the pivotal Phase III study of the candidate malaria vaccine RTS,S/AS01E
(Malaria-055), two consecutive vaccine safety monitoring studies (EPI-MAL-002 and 
EPI-MAL-003) will be conducted to monitor incidence rates of meningitis, protocol 
defined adverse events of specific special interest (AESI) and non-communicable and 
non-traumatic serious other adverse events (NC/NT-SAE).leading to hospitalisations 
and death. The first study, EPI-MAL-002, is a surveillance study prior to RTS,S/AS01E
authorisation in the country; the second study, EPI-MAL-003, will more specifically 
monitor RTS,S/AS01E safety and will only start when RTS,S/AS01E is registered and 
authorised in the country. The planned age range for licensure of the RTS,S/AS01E
candidate vaccine is in children from 6 weeks of age to less than18 months. The 
secondary endpoints of these studies include monitoring the incidence of malaria disease 
as diagnosed during out-patient visits or hospitalisation. Up to seven Health and
Demographic Surveillance System (HDSS) (or equivalent system) sites in five different
countries in Sub-Saharan Africa will participate in these studies, enrolling approximately 
4030 000 children <35 years of age in each study EPI-MAL-002 and approximately 45 
000 children <5 years in EPI-MAL-003.
This epidemiology study (EPI-MAL-005) is planned to run in parallel with these two 
studies, enrolling from the same HDSS (or equivalent system) populations. 
Although not yet considered as the global gold standard, NAAT-based (nucleic acid 
amplification test) techniques can detect infections of lower malaria parasite density and 
give more accurate quantification of parasitaemia than is achievable by microscopy. 
Identification of gametocytes by microscopy is inherently challenging, thus their 
presence is often missed, even by highly trained technicians. Therefore, additional 
analysis of collected blood samples by NAAT will allow for the detection of lower 
density parasite infections and will be a more sensitive measure of changes in both
parasite and gametocyte prevalence and density, thereby providing greater insight into 
potential changes upon vaccine implementation. This will also provide comparability of 
data collected in this study with the technique likely to be favoured in clinical trials in the 
future.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
78
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
79
2
OBJECTIVES
2.2
Secondary objectives

To estimate longitudinal trends in receipt and timing of the third dose of 
DTP/HepB/Hib pentavalent and the first dose of measles EPI vaccines, at around 14 
weeks and 9 months of age respectively, as appropriate by country.
2.3
Tertiary objectives

To compare asexual and sexual (gametocyte) parasitaemia (qualitative and semi-
quantitative-density) when measured by microscopy or NAAT in the RTS,S/AS01E
vaccinated and unvaccinated subjects.

To compare asexual and sexual (gametocyte) parasitaemia (qualitative- and semi-
quantitative-density) when measured by microscopy or NAAT.
3
STUDY DESIGN OVERVIEW

Biological Samples: A capillary blood sample will be obtained for evaluation of 
malaria infection by blood slide and NAAT. In the event of measured fever at the 
time of the visit (axillary temperature ≥37.5°C) or fever reported in the last 24 hours 
or other symptoms/signs of clinical malaria, a rapid diagnostic test (RDT) will be 
conducted. If the RDT is positive, treatment will be given according to National 
guidelines. If a subject for whom no RDT was required is identified as being parasite 
positive following microscopy, National guidelines should be followed for clinical 
management of the subject.
Using Geographic Information System (GIS) to determine geographical variability in 
MTI locally: Study areas will be mapped by villages using grid referencing.

This study will involve up to 59 annual cross sectional surveys during malaria peak 
transmission.

Duration of the study: up to 59 years
NOTE: surveys may not be in consecutive years and the total will then be less than 5.

Epoch 006: Survey 6 at Year 6.

Epoch 007: Survey 7 at Year 7.

Epoch 008: Survey 8 at Year 8.

Epoch 009: Survey 9 at Year 9
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
79
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
80
Table 1
Study groups and epochs foreseen in the study 
Study 
Group
Age 
(Min/M
ax)
No 
of 
site
s
Total 
no of 
subject
s
Total no of 
subjects/sit
e
Epochs
Epoch 
001 
Survey 
1
Epoch 
002 
Survey 
2
Epoch 
003 
Survey 
3
Epoch 
004 
Survey 
4
Epoch 
005 
Survey 
5
Epoch 
006 
Survey 
6 
Epoch 
007 
Survey 
7 
Epoch 
008 
Survey 
8 
Epoch 
009 
Survey 
9 
Total
Study 
site
6 
months 
/ 9 
years 
7
2100
3000
420060
0 
subject
s
4200
600 
subject
s
420060
0 
subject
s
4200
600 
subject
s
420060
0 
subject
s
600 
subject
s
600 
subject
s
600 
subject
s
600 
subject
s
3.1
Discussion of study design
Up to 5 Nine annual cross sectional surveys at peak transmission will provide point 
estimates of parasite prevalence and subsequently a longitudinal assessment of the level 
of endemicity in each area covered by EPI-MAL-002 and EPI-MAL-003. Malaria 
transmission is highly seasonal so surveys will be carried out at during the end course of 
the rainy season preferably when rains decrease, the period of highest malaria 
transmission.
4
STUDY POPULATION
4.1
Number of subjects/ centres
Subjects 6 months to <10 years of age will be enrolled in HDSS (or equivalent system)
catchment areas at the sites participating in the EPI-MAL-002 and EPI-MAL-003 studies 
of the candidate malaria vaccine RTS,S/AS01E in sub-Saharan Africa. Up to 7 seven
HDSS (or equivalent system) sites will are planned to participate in this study (see 
Section 4.1.1). Subjects enrolled in EPI-MAL-002 and EPI-MAL-003 are eligible for 
participation in this study.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
80
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
81
Each study site will enroll approximately 600 subjects per survey. These subjects will be 
selected at random from the HDSS (or equivalent system) population listings prepared 
at each site. The selection process will be repeated every year meaning that the subjects 
will be different in each cross-sectional survey except if they are re-selected in a 
subsequent survey by chance. The population listings generated from the demographic 
surveillance will allow for sampling of the required subjects according to stratification by 
age group as follows (all subject numbers are approximately plus or minus 5 children): 
Therefore, the total expected sample size over 5 surveys per site and by survey is a 
maximum of 14000 400 subjects aged 6 months to <5 years and a maximum of 7000
200 subjects aged 5 to <10 years, calculated as follows:

Subjects aged 6 months to <5 years: max 5 study years x 7 sites x 400 subjects = 
max 14000 subjects

Subjects aged 5 to <10 years: max 5 study years x 7 sites x 200 subjects = max 7000 
subjects.
4.1.1
Recruitment of study centres/ investigators 
All HDSS (or equivalent system) study sites participating in EPI-MAL-002 and EPI-
MAL-003 will be approached with regard to participation in this epidemiological study. 
At the time of original protocol finalisation, these comprised centres sites in Burkina 
Faso, Ghana, Senegal, Tanzania, and Kenya (APPENDIX A).
The study sites will be revised after survey 2. Following the World Health Organization 
(WHO)’s Strategic Advisory Group of Experts (SAGE) on Immunization and the 
Malaria Policy Advisory Committee (MPAC) recommendations of pilot 
implementations of RTS,S/AS01E in 3-5 distinct settings in sub-Saharan Africa (SSA) 
restricted to moderate-to-high transmission of malaria, other settings in SSA with 
moderate-to-high transmission of malaria might be added to the already defined 
EPI-MAL-002 and EPI-MAL-003 study sites. These new sites will also be added to the 
EPI-MAL-005 study.
The study sites in Senegal and Tanzania with low malaria transmission will no longer 
participate in the study after Survey 2.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
81
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
82
4.1.2
Sampling methods
All participating centres will have a HDSS (or equivalent system) in place. In general, 
any variation in sampling procedure should follow as closely as possible the Guidelines 
of the Roll Back Malaria Monitoring and Evaluation Reference Group [2005]. The 
following steps serve as an example of a sampling method.
1.
Generate a list from the HDSS (or equivalent system) database of all children aged 6 
months to <10 years.
Each study site will enrol approximately 600 subjects per survey. To allow for 10% 
non-response 660 subjects should therefore be randomly selected from the HDSS (or 
equivalent system) database distributed over all age categories as described in Section 
4.1.
5.4
Outline of study procedures
Table 2 details study procedures to be conducted during the study.
Table 2
List of study procedures to be conducted at each survey visit 
Epoch
Epoch 
001
Epoch 
002
Epoch 
003
Epoch 
004
Epoch 
005
Epoch 
006
Epoch 
007
Epoch 
008
Epoch 
009
Study Group1
Survey 
1
Survey 
2
Survey 
3
Survey 
4
Survey 
5
Survey 
6
Survey 
7
Survey 
8
Survey 
9
Timepoint
Year 1 Year 2 Year 3
Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 
Informed consent
●
●
●
●
●
●
●
●
●
Check inclusion/exclusion criteria
●
●
●
●
●
●
●
●
●
Record demographic details
●
●
●
●
●
●
●
●
●
Record subject’s vaccination status2
●
●
●
●
●
●
●
●
●
Record any anti-malarial medication or 
other medication received within the 
previous 14 days
●
●
●
●
●
●
●
●
●
Record relevant medical history 
(hospitalisation, reported fever, and 
care seeking behaviour)
●
●
●
●
●
●
●
●
●
Record axillary body temperature
●
●
●
●
●
●
●
●
●
Record malaria control measures 
used in the household
●
●
●
●
●
●
●
●
●
Record malaria prevention and risk 
factors
●
●
●
●
●
●
●
●
●
Take capillary blood sample (up to 
500 μL)3
●
●
●
●
●
●
●
●
●
Assessment of RDT4
●
●
●
●
●
●
●
●
●
Study conclusion
●
●
●
●
●
●
●
●
●
● is used to indicate a study procedure that requires documentation in the individual eCRF.
1.
The new sites will join the study after survey 3, depending on when they are included in EPI-MAL 002/ 003. 
The total surveys at these new sites will therefore be less than 9. Surveys may not be in consecutive years 
and the total will then be less than 5
2.
RTS,S/AS01 and 3rd dose DTP/HepB/Hib and first dose measles EPI vaccinations, only
3.
Capillary blood sample for determination of parasite prevalence (blood slides and NAAT by filter paper)
4.
Only In the event of measured fever at time of visit (axillary temperature ≥37.5°C) or fever reported in last 24 
hours or other symptoms/signs of clinical malaria, a rapid diagnostic test (RDT) will be conducted using 
capillary blood sample taken for blood slide preparation.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
82
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
83
Table 3
List of study procedures to be conducted during survey 
Epoch
Epoch 
001
Epoch 
002
Epoch 
003
Epoch 
004
Epoch 
005
Epoch 
006
Epoch 
007
Epoch 
008
Epoch 
009
Study Group1
Survey 
1
Survey 
2
Survey 
3
Survey 
4
Survey 
5
Survey 
6
Survey 
7
Survey 
8
Survey 
9
Timepoint
Year 1
Year 2 
Year 3 
Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 
Site specific information collection -
Meteorological data (if available)
1
●
●
●
●
●
●
●
●
●
Site specific information collection –
Malaria Control Programme
●
●
●
●
●
●
●
●
●
● is used to indicate a study procedure that requires documentation in the individual eCRF.
Surveys may not be in consecutive years and the total will then be less than 5. Availability of meteorological data will 
be based on the site having the weather station. All sites received weather stations either post Survey 1 or 2.
5.5.4
Check and record medications/vaccinations
Record RTS,S/AS01E (all doses) and other vaccinations (i.e. 3rd dose DTP/HepB/Hib
pentavalent and first dose measles EPI vaccinations) administered, including dates. The 
vaccination status will be recorded in the eCRF. 
5.5.7
Collect data on malaria control interventions
Record the following malaria control measures in the subject’s eCRF:

Residual spraying, mosquito net usage, seasonal malaria chemoprevention (SMC), 
intermittent preventative preventive treatment in infants (IPTi), and ACT all anti-
malaria therapy received within the last 14 days. 
5.5.9
Capillary blood sampling 
A capillary blood sample (up to 500µL), collected by finger/heel prick, will be taken 
during the study visit for the assessment of parasitaemia (see Section 5.6.2). The 
following biological samples will be taken at each survey visit:

Blood for asexual and sexual (gametocyte) microscopy (2 slides [up to 4 slides might 
be prepared according to study site standard operating procedures (SOPs)]: 
approximately 2 drops on each microscope slide).
In the event of measured fever at the time of the visit (axillary temperature ≥37.5°C) or 
fever reported in last 24 hours or other symptoms/signs of clinical malaria, a RDT will 
also be conducted using the capillary blood sample.
5.5.10 Site specific information collection
All sites received a weather station either post Survey 1 or Survey 2.
5.6
Biological sample handling and analysis

It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed when signing the Informed Consent 
Form will be invited to give another specific consent to allow GSK or a contracted 
partner to use the samples for future research including development of tests and 
their quality assurance.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
83
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
84
5.6.2
Biological samples
Table 4
Biological samples
Sample type
Quantity
Sample 
volume (max)
Timepoint
Whole blood
Approximately 1 drop
(RDT assessment )*
0.06 
Survey Visit
Whole blood
Approximately 4 drops; 1 drop for the thin smear and up to 3 
drops for the thick smear up to 2 drops on each microscope 
slide (merozoite and gametocyte microscopy assessment)
0.24 mL 
Survey Visit
Whole blood
Approximately 2 to 3 drops; filter paper collection 
parasite and gametocyte NAAT assessment)
0.12 mL 
Survey Visit
RDT = Rapid Diagnostic Test
NAAT = Nucleic Acid Amplification Test
*Only in In the event of measured fever at time of visit (axillary temperature ≥37.5°C) or reported fever in last 24 
hours or other symptoms/signs of clinical malaria.
5.6.3
Laboratory assays
Please refer to APPENDIX B APPENDIX A for a detailed description of the assays 
performed in the study. Please refer to APPENDIX C APPENDIX B for the address of 
the clinical laboratories used for sample analysis.
In the event of fever measured at time of visit (axillary temperature ≥37.5°C) or reported 
fever in last 24 hours or other symptoms/signs of clinical malaria, a RDT will be 
conducted. The clinical management of subjects presenting with malaria as identified by 
RDT or microscopy will follow National guidelines. Subjects will receive appropriate 
care according to standard clinical practice.
All blood slides with thick and thin smears will be made in duplicate. In the study sites 
where study site SOPs require the preparation of separate thin and thick smears, up to 4 
blood slides might be prepared. One slide with thick and thin smears, or two slides with 
separate thick and thin smears, will be sent for storage to a GSK dedicated laboratory 
facility and the remaining slide(s) will be stored at the study site. For each slide, 
parasitaemia will be determined independently by two readers and in the case of non-
concordance an additional read by a third independent reader will be carried out. Since 
there will be no full blood count performed in the study subjects the used methodology 
for the determination of P. falciparum asexual parasite density may be based on an 
assumed white cell count of 8000/µL. Please refer to APPENDIX B APPENDIX A for a 
description of other methodologies for the determination of P. falciparum asexual 
parasite density. 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
84
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
85
7.1.2
Secondary endpoints

Occurrence of uptake and timing of the third dose of DTP/HepB/Hib pentavalent
and the first measles EPI vaccines 
Criteria/definitions: vaccination record of receipt of dose 3 of the DTP/HepB/Hib
pentavalent and the first dose of the measles EPI vaccines.
7.2.3
Children aged 5 to < 10 years
Since the precision of 0.25 was adequate and determined for the WHO (children aged 6 
months to <5 years) and JTEG (children aged 2 to <10 years) definitions, the sample 
size for the subgroup of children 5-9 years was fixed at 200 which gives a relative 
standard error equal to a maximum of 0.35. In addition, it is anticipated that children 
in this older age group are more likely to be at school and it may take longer to recruit 
this age group with subsequent logistics and financial implications.
7.7.1.1 Overall
First the trends in parasite prevalence between each cross-sectional malariometric surveys 
will be tested using the Cochran-Armitage trend test [Agresti, 1990]. This hypothesis test 
will be performed on the parasite prevalence computed on the independent samples of 
subjects in each survey, within each site separately.
7.7.1.2.1
Annual fluctuations: vaccine ineligible subgroup
Once the cross-surveys are collected, the independent samples of subjects in each survey 
will be tested and assessed using a Chi-square statistic to test the significance of the 
differences among the parasite prevalences in each survey; meaning annual fluctuations.
7.7.2
Other prevalences and proportions
Prevalence estimate for each segment will be estimated using the following criteria for 
level of endemicity: ‘high’ ≥ 60%, ‘moderate’ 20%-59%, and ‘low’ <20% relating to the 
proportion of infected children in each segment [Snow 1997; Omumbo 1998]. 
The proportion of subjects having received the third dose of DTP/HepB/Hib pentavalent
and the first dose of measles EPI vaccine will be estimated as the ratio of the subjects 
having received the third dose of DTP/HepB/Hib pentavalent and the first dose of 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
85
14-SEP-2018
CCI

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
86
measles EPI vaccine divided by the number of subjects who should have received the 
third dose of DTP/pentavalent and the first dose of measles EPI (i.e. 14 weeks and 9 
months of age, respectively). Moreover, among the subjects having received the third 
dose of DTP/HepB/Hib pentavalent and the first dose of measles EPI vaccine, the 
proportions of subjects having received them on time, in advance and with delay will be 
estimated. 
7.8
Analysis of tertiary objectives
The comparisons of asexual and sexual (gametocyte) parasitaemia measured by 
microscopy and NAAT will be done using Cohen’s Kappa coefficient Fisher’s exact test. 
The hypothesis test will be done per centre, and overall. No correction for multiple 
testing will be done.
7.10.1 Sequence of analyses
Statistical reports will be written after each epoch. A clinical report will be written after 
each epoch by GSK Surveys 2 and 5 and an integrated report will be written at the end 
of the study.
APPENDIX A
STUDY SITES
PI Last Name
PI First 
Name
Country- Study Site
Location
Owusu-Agyei
Seth
GHANA - KINTAMPO
Kintampo Health Research Centre
Kintampo
GHANA
Otieno
Walter
KENYA - KOMBEWA
Walter Reed Project - Kombewa Clinical Research 
Centre
Opposite Kisumu West District Hospital
Kisumu Bondo Road
Kisumu 
KENYA
Lusingu
John
TANZANIA -
KOROGWE
Joint Malaria Programme (JMP)
Korogwe District Hospital, New Laboratory Building, 
Korogwe, Tanga
TANZANIA
Gaye
Omar
SENEGAL – KEUR 
SOCE
Centre de Recherche de Keur Socé
Departement de Parasitologie
Faculté de Médecine
Université Cheikh Anta Diop, Dakar
SENEGAL
Sokhna 
Cheikh-S
SENEGAL - NIAKHAR
UMR 198 URMITE
Unite de Recherche sur les Maladies Infectieuses et 
Tropicales Emergentes
Campus commun IRD-UCAD de Hann 
BP 1386 CP 18524 Dakar 
SENEGAL
Bienvenu 
Sirima
Sodiomon
BURKINA FASO -
SAPONE
Centre National de recherche et de 
Formation sur le paludisme (CNRFP)
01 BP 2208 Ouagadougou 01
BURKINA FASO
Sie
Ali
BURKINA FASO -
NOUNA
Centre de Recherche en Santé de Nouna, 
PO BOX 02 Nouna
BURKINA FASO
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
86
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
87
APPENDIX A
APPENDIX C B
CLINICAL LABORATORIES
Table 10
Outsourced laboratories
Laboratory
Address
Koninklijk Instituut voor de Tropen (KIT) (Royal Tropical 
Institute) Academic Medical Center (AMC)
Laboratory for clinical parasitology, L1-247 
Department of Medical Microbiology
Meibergdreef 39 9 
1105 AZ Amsterdam
The Netherlands
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
87
14-SEP-2018
CCI

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
88
GlaxoSmithKline Biologicals SA
Vaccines R & D
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
116682 (EPI-MALARIA-005 BOD AME)
Amendment number:
Amendment 2
Amendment date:
14 September 2018
Co-ordinating author:
, Freelance Science Writer for GSK 
Biologicals
Rationale/background for changes: 
A delay in the implementation of the RTS,S/AS01E vaccine in the 3 countries 
participating in the World Health Organisation (WHO)-led Malaria Vaccine 
Implementation Programme (MVIP) has resulted in a delay to the start of EPI-MAL-
003. As a consequence, EPI-MAL-005, being an ancillary study to EPI-MAL-003, will 
need to be extended in order to mirror the EPI-MAL-003 timeline. The need for an 
additional survey is the trigger for the second amendment of this protocol. Additional 
revisions to the protocol are listed below. 
1.
The current protocol – protocol amendment 1 - currently details 9 annual surveys 
with study duration of up to 9 years. The study will include at least 1 further 
annual survey, lasting for at least 10 years in total. Thus, the longest participating 
sites will perform the study for at least 10 years meaning 10 surveys, whilst some 
sites joining later will not perform as many surveys. Protocol text has been revised 
accordingly.
2.
Country and study site participation have changed during the course of the study 
following WHO recommendations for pilot implementation of RTS,S/AS01E in 
settings with moderate-to-high transmission of malaria and WHO Regional Office 
for Africa selection for the initial introduction of RTS,S/AS01E in 3 countries 
(Ghana, Kenya and Malawi) through the MVIP. EPI-MAL-003 study site selection 
will be performed following Ministries of Health pre-selection and according to 
WHO guidance in the framework of the MVIP, to include 4 sites in each of the 3 
countries selected for the MVIP. Being an ancillary study to EPI-MAL-002 and 
EPI-MAL-003 studies, EPI-MAL-005 is/will be conducted in study sites 
conducting EPI-MAL-002 and/or EPI-MAL-003. Clarification on the countries 
and sites participating in the study has been provided.
3.
In response to a Corrective and Preventive Action following a Critical Quality 
Attributes audit conducted in Kintampo, Ghana, reference to study conduct in 
accordance with ‘Good Pharmacoepidemiology Practices (GPP) guidelines’ has 
been added to Section 5.1 ‘Regulatory and ethical considerations, including the 
informed consent process’ to align with STD-POL-GSKF-408, and additionally
protocols EPI-MAL-002 and EPI-MAL-003.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
88
14-SEP-2018
PPD

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
89
4.
Vaccine eligible and ineligible subgroups were defined based on assumptions on 
the duration of follow-up of the EPI-MAL-005 study and date of vaccine 
implementation. This amendment primarily documents the extension of the study 
for at least 1 further survey. Furthermore, the date of implementation of the 
vaccine has yet to be confirmed. It is therefore not possible to apply these 
assumptions and the applicable text in Section 7.7.1.2 ‘By vaccine 
eligible/ineligible subgroup: Statistical analyses for vaccine association 
adjustments and association between vaccine and transmission’ has been revised.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Contributing authors
………….

, Clinical Manager Safety 
Physician

, 
 
Senior Manager, Global Study Management

/ 
, Clinical 
Laboratory Sciences-SM Business and Decision Life 
Sciences / external consultant for GSK Biologicals
…………..

, Local Delivery Lead

, external consultant for GSK 
Biologicals
……………….

, Study Delivery Lead, 
SynteractHCR Benelux NV Synteract® for GSK 
Biologicals

, Lead Epidemiologist-Malaria, Aixial 
for GSK Biologicals
…………..

, Senior Lead Epidemiologist-Malaria

, Study Data Manager, TCS for GSK 
Biologicals

, Clinical & Epidemiology Project 
Lead, DDW Vaccines

, Senior Local Delivery Lead 
………………

, Oversight Data Manager, Business and 
Decision Life Sciences for GSK Biologicals

 and 
 Study Data 
Manager

, Study Statistician
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
89
14-SEP-2018
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
90
GSK Biologicals’ protocol template for observational studies and interventional studies 
without administration of medicinal products as described in a research protocol based 
on the Protocol Document Standard version 14.1.2
Copyright 2014-2016 of the GlaxoSmithKline ©2018 GSK group of companies or 
its licensor. All rights reserved. Unauthorised copying or use of this information is 
prohibited.
Protocol Amendment 2 Investigator Agreement
I agree:

………..

To assume responsibility for the proper conduct of the study at this the site(s). 
SYNOPSIS
Rationale for the 
study 
Following the pivotal Phase III study of the candidate malaria 
vaccine RTS,S/AS01E (Malaria-055), two consecutive vaccine 
safety monitoring studies (EPI-MAL-002 and EPI-MAL-003) 
will be conducted to monitor incidence rates of meningitis, 
protocol defined adverse events of specific specific interest 
(AESI), and of other adverse events leading to hospitalisation 
or death, in children. The first study, EPI-MAL-002, is a 
baseline surveillance study prior to RTS,S/AS01E
authorisation in the country; the second study, EPI-MAL-003, 
will more specifically monitor RTS,S/AS01E safety, as well 
as vaccine effectiveness and impact, and will only start when 
RTS,S/AS01E is registered and authorised and implemented
in the country. The World Health Organiszation’s (WHO’s)
Strategic Advisory Group of Experts (SAGE) on 
Immunization and the Malaria Policy Advisory Committee 
(MPAC) recommended pilot implementations of 
RTS,S/AS01E in children of 5–17 months of age, in parts of 3-
5 sub-Saharan African (SSA) countries, administering 3 doses 
of the vaccine to children aged 5-9 months of age in areas of
moderate-to-high transmission of malaria with a fourth dose 
15-18 months later. The first vaccine introduction is foreseen 
in 2018. The secondary endpoints of these studies also include 
monitoring the incidence of malaria disease as diagnosed 
during out-patient visits or hospitalisation. Up to seven Health 
and Demographic Surveillance System (HDSS) (or equivalent 
system) sites1 in countries in Ssub-Saharan Africa will 
participate in these studies, enrolling approximately 30 000 
children <5 years of age in EPI-MAL-002 and approximately 
45 000 children <5 years in EPI-MAL-003.
This epidemiology study (EPI-MAL-005) is planned to run in 
parallel with these two studies, enrolling from the same HDSS 
(or (equivalent system) populations. The primary objectives of 
this study are to produce longitudinal estimates of parasite 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
90
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
91
prevalence in humans, and record malaria control measure
usage in areas where EPI-MAL-002 and EPI-MAL-003 
studies will take place.……………..
Outside of the controlled setting of a clinical trial, there is the 
risk that usage of malaria control interventions such as indoor
residual spraying and bednets may change following vaccine
introduction. ……………
1 Throughout the document, the terms of site, cluster and centre are used interchangeably, having the 
same meaning.
Study design

Type of design: A multi-centric, epidemiology 
longitudinal cross-sectional study at centres in Ssub-
Saharan Africa that are participating in GSK's 
EPI-MAL-002 and EPI-MAL-003 studies.

……………….

Using Geographic Information System (GIS) to 
determine geographical variability in MTI locally: Study 
areas will be mapped by villages using grid referencing. 
Subjects will be attributed to their village, however, to 
avoid PII (personally identifiable information); small 
villages will be grouped when the number of participants 
is less than 10, such so that it is not possible to identify 
one subject from one village. ………..

………………

This study will involve up to 9 10 annual cross sectional 
surveys during malaria peak transmission with possible 
further extension, dependent on the duration of the 
EPI-MAL-002 and EPI-MAL-003 studies.

Duration of the study: up to 9 10 years with possible 
further extension, dependent on the duration of the 
EPI-MAL-002 and EPI-MAL-003 studies:

………………..

Epoch 010: Survey 10 at Year 10
Synopsis Table 1
Study groups and epochs foreseen in the study 
Study 
Group
Age 
(Min/Max)
Epochs
Epoch 
001
Survey 
1
Epoch 
002
Survey 
2
Epoch 
003
Survey 
3
Epoch 
004
Survey 
4
Epoch 
005
Survey 
5
Epoch 
006 
Survey 
6
Epoch 
007
Survey 
7
Epoch 
008
Survey 
8
Epoch 
009
Survey 
9
Epoch 
010
Survey 
10
Study 
site
6 months / 
9 years
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
91
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
92
Discussion of study 
design
………….
Nine At least 10 annual cross sectional surveys at peak 
transmission will provide point estimates of parasite prevalence 
and subsequently a longitudinal assessment of the level of 
endemicity in each area covered by EPI-MAL-002 and 
EPI-MAL-003. …………
Endpoints
Primary

Occurrence of P. falciparum parasitaemia (using 
microscopy)
Criteria/definitions: infection with P. falciparum 
determined using a blood smear slide and determined using 
microscopy.

Occurrence of malaria control interventions
Criteria/definitions: malaria control interventions are 
mosquito net usage (including insecticide-treated nets 
[ITN] and long lasting insecticidal nets [LLIN]), indoor
residual spraying (IRS), seasonal malaria chemoprevention 
(SMC), intermittent preventative treatment in infants (IPTi),
and ACT therapy received within the last 14 days.
LIST OF ABBREVIATIONS
AESI
Adverse events of specific special interest
GPP
Good Pharmacoepidemiology Practice
LLIN
Long lasting insecticidal nets
MVIP
Malaria Vaccine Implementation Programme
GLOSSARY OF TERMS
Malaria control 
interventions:
Any intervention or control measure targeted at reducing 
malaria transmission or preventing malaria disease 
[World Health Organisation, 2013]. This includes ITN, 
LLIN, IRS, SMC, IPTi, IPTp and ACTs. 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
92
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
93
1.2
Rationale for the study
Following the pivotal Phase III study of the candidate malaria vaccine RTS,S/AS01E
(Malaria-055), two consecutive vaccine safety monitoring studies (EPI-MAL-002 and 
EPI-MAL-003) will be conducted to monitor incidence rates of meningitis, protocol 
defined adverse events of special specific interest (AESI), and of other adverse events 
leading to hospitalisations and or death, in children. The first study, EPI-MAL-002, is a 
baseline surveillance study prior to RTS,S/AS01E authorisation in the country; the 
second study, EPI-MAL-003, will more specifically monitor RTS,S/AS01E safety, as 
well as vaccine effectiveness and impact, and will only start when RTS,S/AS01E is 
registered and authorised and implemented in the country. The World Health 
Organisation’s (WHO’s) Strategic Advisory Group of Experts (SAGE) on 
immunization and the Malaria Policy Advisory Committee (MPAC) recommended pilot 
implementations of RTS,S/AS01E in children of 5–17 months of age, in parts of 3-5 
sub-Saharan African (SSA) countries, administering 3 doses of the vaccine to children 
aged 5-9 months of age in areas of moderate-to-high transmission of malaria with a 
fourth dose 15-18 months later. The first vaccine introduction is foreseen in 2018. The 
planned age range for licensure of the RTS,S/AS01E candidate vaccine is in children 
from 6 weeks of age to less than18 months. The secondary endpoints of these studies also
include monitoring the incidence of malaria disease as diagnosed during out-patient visits 
or hospitalisation. Up to seven Health and Demographic Surveillance System (HDSS) (or 
equivalent system) sites2 in different countries in Ssub-Saharan Africa will participate in 
these studies, enrolling approximately 30 000 children <5 years of age in EPI-MAL-002 
and approximately 45 000 children <5 years in EPI-MAL-003.
…………..
Outside of the controlled setting of a clinical trial, there is the risk that usage of malaria 
control interventions such as indoor residual spraying and bednets may change following 
vaccine introduction. ……….
2 Throughout the document, the terms of site, cluster and centre are used interchangeably, having the 
same meaning.
3.
STUDY DESIGN OVERVIEW
……………

Type of design: A multi-centric, epidemiology longitudinal cross-sectional study at 
centres in Ssub-Saharan Africa that are participating in GSK's EPI-MAL-002 and 
EPI-MAL-003 studies.

……………….

Using Geographic Information System (GIS) to determine geographical variability in 
MTI locally: Study areas will be mapped by villages using grid referencing. Subjects 
will be attributed to their village, however, to avoid PII (personally identifiable 
information), small villages will be grouped when the number of participants is less 
than 10, such so that it is not possible to identify one subject from one village. ….
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
93
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
94

………………

This study will involve up to 9 10 annual cross sectional surveys during malaria peak 
transmission with possible further extension, dependent on the duration of the 
EPI-MAL-002 and EPI-MAL-003 studies.

Duration of the study: up to 9 10 years with possible further extension, dependent 
on the duration of the EPI-MAL-002 and EPI-MAL-003 studies:

…………

Epoch 010: Survey 10 at Year 10
Table 1
Study groups and epochs foreseen in the study
Study 
Group
Age 
(Min/Max)
Epochs
Epoch 
001
Survey 
1
Epoch 
002
Survey 
2
Epoch 
003
Survey 
3
Epoch 
004
Survey 
4
Epoch 
005
Survey 
5
Epoch 
006 
Survey 
6
Epoch 
007
Survey 
7
Epoch 
008
Survey 
8
Epoch 
009
Survey 
9
Epoch 
010
Survey 
10
Study 
site
6 months / 
9 years
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
600
subjects
3.1.
Discussion of study design
………..
Nine At least 10 annual cross sectional surveys at peak transmission will provide point 
estimates of parasite prevalence and subsequently a longitudinal assessment of the level 
of endemicity in each area covered by EPI-MAL-002 and EPI-MAL-003. ……….
4.1.
Number of subjects/ centres
Subjects 6 months to <10 years of age will be enrolled living in HDSS (or equivalent 
system) catchment areas at of the sites participating in the EPI-MAL-002 and EPI-MAL-
003 studies of the candidate malaria vaccine RTS,S/AS01E in sub-Saharan Africa are 
eligible for enrolment. Up to seven HDSS (or equivalent system) sites are planned to 
participate in this study (see Section 4.1.1). Subjects already enrolled in EPI-MAL-002 
and EPI-MAL-003 are eligible for participation in this study.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
94
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
95
4.1.1 Recruitment of study centres / investigators 
All HDSS (or equivalent system) study sites participating in EPI-MAL-002 and EPI-
MAL-003 will be approached with regard to participation in this epidemiological study. 
The ancillary EPI-MAL-005 study will be conducted in sites defined in the 
EPI-MAL-002 and EPI-MAL-003 protocols. At the time of original protocol 
finalisation, identified study sites were located these comprised sites in Burkina Faso, 
Ghana, Kenya, Senegal, and Tanzania, and Kenya.
The study sites will be revised after survey 2. Following the World Health Organization 
(WHO)’s Strategic Advisory Group of Experts (SAGE) on immunization and the Malaria 
Policy Advisory Committee (MPAC) recommendations of pilot implementations of 
RTS,S/AS01E in 3-5 distinct settings in sub-Saharan Africa (SSA) restricted to 
moderate-to-high transmission of malaria, other settings in SSA with moderate-to-high 
transmission of malaria might be added to the already defined EPI-MAL-002 and EPI-
MAL-003 study sites. These new sites will also be added to the EPI-MAL-005 study. site 
selection in some of the initially chosen EPI-MAL-002, EPI-MAL-003 and EPI-MAL-
005 study sites located in low endemicity settings (i.e. in Senegal and Tanzania) had to 
be terminated. In April 2017, the WHO Regional Office for Africa announced that the 
RTS,S/AS01E vaccine will be first introduced in 3 countries (Ghana, Kenya and 
Malawi) through the Malaria Vaccine Implementation Programme (MVIP). Selection 
of the clusters that are/will participate in GSK’s baseline, Phase IV and ancillary 
studies (i.e. EPI-MAL-002, EPI-MAL-003 and EPI-MAL-005, respectively), being fully 
embedded in the MVIP, depends on the cluster identification process led by the 
Ministries of Health according to WHO guidance. They have been, or will be, selected 
as follows:

Sites have been, or will be, selected from the 3 countries where the RTS,S/AS01E
vaccine will be implemented (Ghana, Kenya and Malawi). Burkina Faso sites that 
started EPI-MAL-005 will early terminate the conduct of the study following 
Survey 4; data from these sites will be presented in the interim report planned 
following Survey 5.

As currently planned in the MVIP and according to WHO guidance, 4 study sites 
(corresponding to 4 clusters of the MVIP) in each of the 3 countries selected for 
the RTS,S/AS01E pilot implementation programme (12 study sites/clusters in total) 
are planned to be part of EPI-MAL-005. 
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
95
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
96

Of note, all study sites are submitted to a comprehensive scientific and operational 
study site assessment conducted by GSK, which will determine study feasibility in 
those sites.
The study sites in Senegal and Tanzania with low malaria transmission will no longer 
participate in the study after Survey 2.
In summary, selection of sites will be performed in EPI-MAL-002 and EPI-MAL-003
studies following Ministries of Health pre-selection and according to WHO guidance, 
to include 4 sites in each of the 3 countries selected for the MVIP. EPI-MAL-005 
is/will be conducted in study sites conducting EPI-MAL-002 and/or EPI-MAL-003.
5.1.
Regulatory and ethical considerations, including the informed 
consent process
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), Guidelines for Good Pharmacoepidemiology Practices (GPP) [ISPE, 
2015], or other applicable guidelines, all applicable subject privacy requirements and the 
guiding principles of the Declaration of Helsinki.
5.4.
Outline of study procedures
Table 2
List of study procedures to be conducted at each survey visit 
Epoch
Epoch 
001
Epoch 
002
Epoch 
003
Epoch 
004
Epoch 
005
Epoch 
006
Epoch 
007
Epoch 
008
Epoch 
009
Epoch 
010
Study Group1
Survey 
1
Survey 
2
Survey 
3
Survey 
4
Survey 
5
Survey 
6
Survey 
7
Survey 
8
Survey 
9
Survey 
10
Timepoint
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6
Year 7
Year 8
Year 9 Year 10
Informed consent
●
●
●
●
●
●
●
●
●
●
Check inclusion/exclusion 
criteria
●
●
●
●
●
●
●
●
●
●
Record demographic 
details
●
●
●
●
●
●
●
●
●
●
Record subject’s 
vaccination status2
●
●
●
●
●
●
●
●
●
●
Record any anti-malarial 
medication or other 
medication received within 
the previous 14 days
●
●
●
●
●
●
●
●
●
●
Record relevant medical 
history (hospitalisation, 
reported fever, and care 
seeking behaviour)
●
●
●
●
●
●
●
●
●
●
Record axillary body 
temperature
●
●
●
●
●
●
●
●
●
●
Record malaria control 
measures used in the 
household
●
●
●
●
●
●
●
●
●
●
Record malaria prevention 
and risk factors
●
●
●
●
●
●
●
●
●
●
Take capillary blood 
sample3
●
●
●
●
●
●
●
●
●
●
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
96
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
97
Epoch
Epoch 
001
Epoch 
002
Epoch 
003
Epoch 
004
Epoch 
005
Epoch 
006
Epoch 
007
Epoch 
008
Epoch 
009
Epoch 
010
Study Group1
Survey 
1
Survey 
2
Survey 
3
Survey 
4
Survey 
5
Survey 
6
Survey 
7
Survey 
8
Survey 
9
Survey 
10
Timepoint
Year 1
Year 2
Year 3
Year 4
Year 5
Year 6
Year 7
Year 8
Year 9 Year 10
Assessment of RDT4
●
●
●
●
●
●
●
●
●
●
Study conclusion
●
●
●
●
●
●
●
●
●
●
Footnotes to Table 2:
● is used to indicate a study procedure that requires documentation in the individual eCRF
1The nNew sites will join the study after survey 3, depending on when they are included in EPI-MAL-002/-003. The total 
surveys at these new sites will therefore be less than 910.
2 RTS,S/AS01 and 3rd dose DTP/HepB/Hib and first dose measles EPI vaccinations, only
3 Capillary blood sample for determination of parasite prevalence (blood slides and NAAT by filter paper)
4 In the event of measured fever at time of visit (axillary temperature ≥37.5°C) or fever reported in last 24 hours or 
other symptoms/signs of clinical malaria, a rapid diagnostic test (RDT) will be conducted using capillary blood sample 
taken for blood slide preparation.
Table 3
List of study procedures to be conducted during survey 
Epoch
Epoch 
001
Epoch 
002
Epoch 
003
Epoch 
004
Epoch 
005
Epoch 
006
Epoch 
007
Epoch 
008
Epoch 
009
Epoch 
010
Study Group
Survey 
1
Survey 
2
Survey 
3
Survey 
4
Survey 
5
Survey 
6
Survey 
7
Survey 
8
Survey 
9
Survey 
10
Timepoint
Year 1
Year 2
Year 3
Year 4 Year 5 Year 6 Year 7 Year 8 Year 9
Year 10
Site specific information 
collection -
Meteorological data 1
●
●
●
●
●
●
●
●
●
●
Site specific information 
collection – Malaria 
Control Programme
●
●
●
●
●
●
●
●
●
●
● is used to indicate a study procedure that requires documentation in the individual eCRF.
1 Availability of meteorological data will be based on the site having the weather station. All sites received weather 
stations either post Survey 1 or 2 or at study start for the new sites.
5.5.7. Collect data on malaria control interventions
Record the following malaria control measures in the subject’s eCRF:

Indoor Rresidual spraying (IRS), mosquito net usage (including insecticide-treated 
nets [ITN] and long lasting insecticidal nets [LLIN]), seasonal malaria 
chemoprevention (SMC), intermittent preventive treatment in infants (IPTi), and all 
anti-malaria therapy received within the last 14 days. 
5.5.10.
Site specific information collection
…………. 
Centre specific information about interventions from the malaria control programme in 
the study area, such as bednet usage (including ITN and LLIN), IRS, RDT, ACT, SMC, 
IPTp and IPTi, will be collected by questionnaire and recorded in a separate database to 
that for subject-specific data.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
97
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
98
7.1.1. Primary endpoints

Occurrence of P. falciparum parasitaemia (using microscopy)
Criteria/definitions: infection with P. falciparum determined using a blood smear 
slide and determined using microscopy.

Occurrence of malaria control interventions 
Criteria/definitions: malaria control interventions are mosquito net usage (including 
insecticide-treated nets [ITN] and long lasting insecticidal nets [LLIN]), indoor
residual spraying (IRS), seasonal malaria chemoprevention (SMC), intermittent 
preventative treatment in infants (IPTi), and ACT therapy received within the last 14 
days. 
7.2.1 Children aged 6 months to <5 years
………….
Up to seven centres will take part in this study. These centres Study sites are in different 
endemicity classes, so a sample of 400 subjects in this age class will allow for suitable 
confidence limits around parasite prevalence estimates for sites within each of the 
endemicity classes.
7.7.1.2.
By vaccine eligible/ineligible subgroup: Statistical analyses for 
vaccine association adjustments and association between vaccine and 
transmission
For the analysis of association between RTS,S/AS01E vaccine and transmission, two 
subgroups must be considered: 

Vaccine eligible subgroup (see glossary of terms for definition). After introduction 
of the vaccine, there will be a catch-up for children less than 18 months old. Taking 
into account the 18 months of follow-up for the vaccine safety study, the oldest 
children vaccinated who could potentially be enrolled could be 3.5 years old. This 
subgroup will be used to assess the association between vaccination and transmission 
intensity, assuming a constant MTI in unvaccinated subjects (which will be 
measured using the second subgroup)..

Vaccine ineligible subgroup (see glossary of terms for definition). Due to the fact 
that the main reservoir of malaria is in the population between 5-20 years old (based 
on data collected in parallel [Epi-Mal-001 study] to the pivotal efficacy Phase III
trial, not published) and MTI will be assessed for up to 2 approximately 5 years 
following the introduction of the vaccine, it will be assumed that there will be 
negligible herd immunity effect. Therefore, this subgroup will be used to detect any 
annual fluctuation (control group). If there is any herd effect, then the vaccine effect 
will be an underestimate.
Assuming a sample size of 600 subjects per centre, and per survey, and a similar sample 
size of children aged 0 to <5 years (JTEG-requested age and MTI reference for 
RTS,S/AS01 vaccine efficacy by research centre-transmission intensity, pending Phase 
III data) and 2 to <10 years (WHO definition [WHO, 1963]); and trying to maximize the 
sample size of the 0-2 year subgroup, it is expected to have 240 subjects in the vaccine 
eligible subgroup and 360 subjects in the vaccine ineligible subgroup.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
98
14-SEP-2018

CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
14-SEP-2018
99
10.  REFERENCES
International Society for Pharmacoepidemiology (ISPE). Guidelines for Good 
Pharmacoepidemiology Practices (GPP). Rev 3 (June 2015). 
http://www.pharmacoepi.org/resources/guidelines_08027.cfm; 2015. Accessed 14 June 
2017.
 
CONFIDENTIAL
116682 (EPI-MALARIA-005 BOD AME)
Protocol Amendment 2 Final
c42dbb0ca4fb5607f68fe513c8686233f98fa2bb
99
14-SEP-2018