A Surveillance Study of Diseases Specified as Adverse Events of Special Interest, of Other Adverse Events Leading to Hospitalisation or Death, and of Meningitis in Children in Africa Prior to Implementation of the RTS,S/AS01E Candidate Vaccine

Study Overview
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Brief Summary
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The purpose of this pre-licensure cohort study is to estimate the incidence of adverse events of special interest (AESI), other adverse events (AE) leading to hospitalisation or death, meningitis and malaria in sub-Saharan African children under 5 years of age. The outcomes of this study will provide the baseline data for the post-licensure EPI-MALARIA-003 (115056) study that will evaluate the safety, effectiveness and impact of the RTS,S/AS01E vaccine. An interim analysis was performed on a sub-group of study participants enrolled in active surveillance from sites where the vaccine is currently implemented, having 6 months of follow-up following the administration of dose 3 of DTP/HepB/Hib vaccine (6-12 weeks group), or 6 months after Visit 3 (mimicking the RTS,S/AS01E primary vaccination schedule) for the 5-17 months group; corresponding to Visit 5. The interim analysis concerned primary safety endpoints and the main secondary endpoints.

Detailed Description
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The outcomes of interest (AESI, other AE leading to hospitalisation or death, and meningitis) as well as data on malaria morbidity and mortality will be captured through active and enhanced hospitalisation surveillance in children less than (<) 5 years of age. Children enrolled in active surveillance will be visited at their home at regular intervals during a period of 44 months. In addition to the home visits, all visits and hospitalisations to health care facilities will be recorded during this period. Thereafter there will be continuous monitoring of hospitalisations only; up to study end or up to the day the child reaches 5 years of age, whichever occurs first. For all children enrolled in enhanced hospitalisation surveillance, all hospitalisation events will be captured during the total study period. The protocol summary has been updated with protocol amendment 4 (dated 11-Dec-2015) information: Rationale for amendment 3: Participant recruitment has been modified: approximately 20,000 children will be enrolled in the active surveillance in the 6-12 weeks group (identified at first administration of DTP/HepB/Hib vaccine), to mimic administration of RTS,S/AS01E in the 6-12 weeks age group, and 20,000 children in the 5-17 months group (either selected children identified at first administration of DTP/HepB/Hib vaccine, or children aged 5 to <18 months and corresponding to a catch-up), to mimic administration of RTS,S/AS01E in the 5-17 months age group. The term passive surveillance has been replaced by the term enhanced hospitalisation surveillance. The case definitions, ascertainment and laboratory investigation (including to determine aetiology) for meningitis cases have been clarified. The objectives and outcomes related to meningitis have been modified accordingly. Case ascertainment for AESI has been clarified. It was clarified that blood sampling is to be performed as per study procedures in case of AESI or meningitis. In case of neurological AESI or meningitis, if a cerebrospinal fluid (CSF) sample is taken as part of routine practice, part of the sample will be stored. Only serious adverse events related to blood sampling will be collected. Limitations due to the sample size and the study design have been further discussed. For clarity, consistency and comparability in the objectives, outcomes and methodologies, protocol amendment 3 text has been aligned in EPI-MALARIA-002 (115055) with the EPI-MALARIA-003 (115056) protocol. Rationale for amendment 4: The background section has been updated with data about cerebral malaria from a post-hoc analysis of the Phase III study MALARIA-055. Additional secondary objectives have been added for estimation of probable meningitis and for estimation of the incidence of cerebral malaria using RDT and/or microscopy. The design and the analysis have been modified to take into account implementation of a 4th dose of RTS,S/AS01E. In addition, the follow-up period after the last dose has been extended to correspond to the follow-up period of the children enrolled in EPI-MAL-003 (i.e. 24 months after the 4th dose of RTS,S/AS01E). Indeed, home visits at 12 months and 24 months after the last RTS,S/AS01E dose will help to capture protocol-defined diseases that may have long risk window periods and that may not have been identified if the subject did not visit a health care facility, and to monitor the occurrence of malaria episodes for evaluation of vaccine effect. The age of the study population has been adapted accordingly (< 5 years). The section about sites participating to the study was updated following SAGE/MPAC recommendations of pilot implementations of RTS,S/AS01E in 3-5 distinct settings in SSA restricted to moderate-to-high transmission of malaria. The activities related to home visits to detect malaria cases, including training of community health workers for systematic measurement of body temperature of all children, and availability of malaria tests have been clarified for alignment with the EPI-MAL-003 protocol. It has been clarified that cases of malaria only detected during the annual visits planned for EPI-MAL-005 will not be included in the analysis of EPI-MAL-002. However, if the cases of malaria are detected during an EPI-MAL-005 home visit that coincides with a home visit scheduled in EPI-MAL-002, the events will be captured in EPI-MAL-002. The case definitions for malaria have been revised, according to the 3rd edition of the WHO guidelines for the treatment of malaria (2015). In addition, a case definition for cerebral malaria has been added. Case ascertainment by the external panel of experts has been clarified. It has been clarified that severe/cerebral malaria cases and other AE leading to hospitalisation or death will be reviewed by the external panel of experts. The incidence of other AE leading to hospitalisation or death, meningitis and malaria morbidity and mortality will be monitored in sub-populations of children with hemoglobinopathies and HIV-positive children. The section about analysis of co-primary objectives has been revised to mention that additional at risk periods will be considered based on results as sensitivity analyses. The section about analysis of secondary objectives has been revised for clarification of potential variables that may be considered for models, in line with information collected in eCRF, and for estimation of the incidence of cerebral malaria. It has been clarified that an interim analysis will be performed with the data collected on all subjects after 6 months of follow-up following the administration of dose 3 of DTP/HepB/Hib vaccine (6-12 weeks group), or 6 months after V3 (5-17 months group). The section about handling of missing data has been revised. It has been clarified that data about seasonal malaria chemoprevention will be collected. Other changes were made for simplification, clarification or consistency. Rationale for amendment 5: In order to have a synergy with the WHO pilot implementation, the study size was reduced from 40,000 to 30,000 children in active surveillance with at least 20,000 children enrolled where the RTS,S/AS01E vaccine will be implemented. Among the 30,000 children, approximately 15,000 children (with at least 10,000 children in sites where the vaccine will be implemented) will be enrolled in the 6-12 weeks group (to collect background data in this age group) and approximately 15,000 children (with at least 10,000 children in sites where the vaccine will be implemented) will be enrolled in the 5-17 months group (to mimic administration of RTS,S/AS01E in the 5-17 months age group). Study size updates involved multiple sections, e.g. Section 9.1 Study Design and Section 9.5 Study size. For multiple sections: the number of countries and number of study sites has been updated following the WHO announcement that the RTS,S/AS01E vaccine will be first introduced in 3 countries (Ghana, Kenya and Malawi) through the MVIP. For multiple sections: estimation of the mortality rate, overall and by gender, has been added. For multiple sections: the informed consent process has been clarified signed or witnessed and thumbprinted ICF. For multiple sections: or equivalent surveillance system has been added after Health and Demographic Surveillance System (HDSS) and the term study site(s) or study area has been added. For multiple sections: the replacement strategy has been updated. For multiple sections: the duration of the recruitment period has been removed, as it could/cannot be respected in all sites due to logistical constraints. For multiple sections: it was clarified that census rounds are scheduled at least once a year during the study periods instead of twice a year. The milestones in Section 6 have been updated. New sub-sections on Severe malaria including cerebral malaria and Overall mortality by gender have been added to Section 7.2 Safety results of the clinical development of RTS,S/AS01E. The wording of secondary objectives on describe the causes of hospitalisation and estimate the incidence of cerebral malaria has been changed, and the secondary objective To describe the causes of death, overall and by gender has been added in Section 8.2 and in the corresponding part of Section 4 Abstract. The opening paragraph of Section 8.2 Secondary Objectives and of the corresponding part of Section 4 Abstract has been updated. The wording of the last two study variables / study endpoints on Occurrence of hospitalisations and Occurrence of death has been modified in Section 9.3.2 and in the corresponding part of Section 4 Abstract. In Section 9.2.1 Study population: the text on Estimated annual birth cohorts by study site (Table 2) has been removed, with removal of planned number of sites in selected countries. Section 9.2.5.3 Meningitis has been edited, including addition of a new opening paragraph, addition of turbid macroscopic aspect as a sign of CSF abnormality, and clarification that clinically suspected meningitis cases included subjects with no CSF sample available and no alternative diagnosis. For consistency between the way the objectives and the endpoints are presented, and to avoid repeating several endpoints, the two sub-sections in Section 9.3.2 Secondary endpoints: In children included in active or enhanced hospitalisation surveillance, prior to implementation of RTS,S/AS01E and In children included in active surveillance, prior to implementation of RTS,S/AS01E have been replaced by one sub-section: In children living in the study area, prior to implementation of RTS,S/AS01E, followed by all the secondary endpoints. In Section 9.4.3 Study EPI-MAL-005 changes in environmental factors such as rainfall has been added to the parameters assessed in EPI-MAL-005. Section 9.5 Study size has been updated as shown in bullet 1 above with greater detail on the estimates of observed incidence of events following dose administration based on either: 15,000 subjects, 10,000 subjects, the estimated birth cohort of 11,500 subjects and an estimated birth cohort of 17,250 children in Tables 6-9. Section 9.7.6 Analysis of secondary safety objectives has been updated, including analysis of cerebral malaria of the causes of death, overall and by gender. Finally, changes in study personnel have been included on the protocol cover page Rationale for amendment 6 Protocol Amendment 6 has been put in place to document that the EPI-MAL-002 study sites in Burkina Faso will early terminate the study and that sites in Malawi, one of the countries where RTS,S/AS01E will be introduced through the MVIP will not take part in the study. GSK, in agreement with WHO, decided to terminate the study EPI-MAL-002 in the two sites located in Burkina Faso, i.e. Nouna and Sapone. Briefly, it was previously decided that Burkina Faso sites would continue participating in EPI-MAL-002 until study end. However, given that the MVIP will not be conducted in this country, there is no scientific value to collect additional data (the EPI-MAL-002 data collected in Burkina Faso will neither be used for the before-after analyses, nor for the generation of EPI-MAL-002 indicators that inform any other analyses of the EPI-MAL-003 study). Therefore, the study EPI-MAL-002 in Burkina Faso sites has been early terminated and data collected and recorded to date in those sites will be reported in a descriptive way. In order to align with the MVIP, the study sites for the GSK Phase IV studies have been selected from the 3 countries where the RTS,S/AS01E vaccine will be implemented (Ghana, Kenya and Malawi). Considering the RTS,S/AS01E vaccine implementation date in Malawi was planned in October 2018, the baseline data that might be collected in Malawi in the EPI-MAL-002 study would be too limited to be relevant for the before/after comparisons in this country. Therefore, GSK, in agreement with the WHO, decided to focus the conduct of the EPI-MAL-002 study in Ghana and Kenya, not initiating the study in Malawi, and partially compensating the expected sample size from Malawi sites by using the high recruitment observed from sites in Kenya (Kombewa) and Ghana (Kintampo) and extending recruitment in Ghana (Navrongo), hence limiting the impact on the before/after comparison study power.

Official Title
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A Prospective Study to Estimate the Incidence of Diseases Specified as Adverse Events of Special Interest, of Other Adverse Events Leading to Hospitalisation or Death, and of Meningitis in Infants and Young Children in Sub-Saharan Africa Prior to Implementation of the RTS,S/AS01E Candidate Vaccine

Conditions
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Malaria, Malaria Vaccines

Intervention / Treatment
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* Procedure: Blood collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects must satisfy ALL the following criteria at study entry: Subjects' parent(s)/Legally Acceptable Representative(s) [LAR(s)] who, in the opinion of the investigator, can and will comply with the requirements of the protocol. Written informed consent provided from either the parent(s) or LAR of the subject. Subject living in the Health and Demographic Surveillance System (HDSS) area. For enrolment in active surveillance: children must be <18 months of age. OR For enrolment in enhanced hospitalisation surveillance: children must be <5 years of age and hospitalised at any time during the study. Exclusion Criteria: Child in care.

Ages Eligible for Study
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Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active surveillance group and enhanced hospitalisation group<br>Children <18 months of age at time of enrolment and living in the HDSS area (active surveillance group) and children <5 years of age and hospitalised at any time during the study, living in the HDSS area (enhanced hospitalisation surveillance group). | Procedure: Blood collection<br>* For all hospitalised children suspected of having an AESI or meningitis, a sample of 5 ml of whole blood is collected and serum is stored.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of AESI | AESI include: Acute Disseminated Encephalomyelitis (ADEM), encephalitis,Guillain Barré Syndrome,hypotonic-hyporesponsive episode,generalised convulsive seizure,intussusception,hepatic insufficiency,renal insufficiency,juvenile chronic arthritis,Stephen-Johnson syndrome/toxic epidermal necrolysis,Henoch-Schonlein purpura,Kawasaki disease,diabetes mellitus type I,thrombocytopenia, anaphylaxis. Incidence rates are calculated by dividing the number of subjects reporting at least one event over the follow-up period by the total person-time.The minimum at-risk period for the analyses is 2 weeks (W).All AESI expected to occur between 0-13 days (D) following dose administration is analysed with an at-risk period of 2 W. The 6W-at-risk period for AESI expected to occur between 14 D-6 W. The 3M and 6M-at-risk periods are for the AESI expected to occur between 6 W-3 M and 3-6 M, respectively. The at-risk period follows any dose, with a censoring of subjects when they receive the following dose. | During the entire study period (From Month 0 up to Month 60) | 
| Incidence of adverse events (AEs) leading to hospitalisation or death | AEs assessed in children <5 years old, included in active or enhanced hospitalisation surveillance, prior to implementation of RTS,S/AS01E. Incidence rates will be calculated by dividing the number of subjects reporting at least one event over the follow-up period by the total person-time. The at-risk periods of 7 days and 30 days will follow any dose, with a censoring of subjects when they receive the following dose. | During the entire study period (From Month 0 up to Month 60) | 
| Incidence of aetiology confirmed meningitis | Aetiology-confirmed meningitis assessment in children <5 years old, living in the study area, prior to implementation of RTS,S/AS01E. Aetiology-confirmed meningitis is defined by the presence of symptoms and/or signs of meningitis and the identification of any known aetiologic agent (bacterial or not) in the CSF. Incidence rates will be calculated by dividing the number of subjects reporting at least one event over the follow-up period by the total person-time. An at-risk period of 12 months after any dose will be used. | During the entire study period (From Month 0 up to Month 60) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of aetiology-confirmed and/or probable meningitis | Aetiology-confirmed and/or probable meningitis assessment in children <5 years old, living in the study area, prior to implementation of RTS,S/AS01E. Aetiology-confirmed meningitis case is defined by the presence of symptoms and/or signs of meningitis and the identification of any known aetiologic agent (bacterial or not) in the CSF. Probable meningitis case is defined by the presence of symptoms and/or signs of meningitis and no aetiologic agent identified in the CSF, but with some abnormalities detected in the CSF (e.g. turbid macroscopic aspect, positive Gram, positive antigen test, pleiocytosis, abnormal glucose or protein levels), or positive blood culture to a bacterial agent. Incidence rates will be calculated by dividing the number of subjects reporting at least one event over the follow-up period by the total person-time. An at-risk period of 12 months after any dose will be used. | During the entire study period (From Month 0 up to Month 60) | 
| Incidence of probable meningitis | Probable meningitis assessed in children < 5 years old, included in active or enhanced hospitalisation surveillance, prior to implementation of RTS,S/AS01E. Incidence rates will be calculated by dividing the number of subjects reporting at least one event over the follow-up period by the total person-time. An at-risk period of 12 months after any dose will be used. | During the entire study period (From Month 0 up to Month 60) | 
| Incidence of aetiology-confirmed, probable and/or clinically suspected meningitis | Aetiology-confirmed, probable and/or clinically suspected meningitis assessment in children <5 years old, living in the study area, prior to implementation of RTS,S/AS01E. Clinically suspected meningitis case is defined by the presence of symptoms and/or signs of meningitis and if a CSF sample is available and all laboratory results are normal after second line laboratory testing, or if no CSF sample is available and no alternative diagnosis. Incidence rates will be calculated by dividing the number of subjects reporting at least one event over the follow-up period by the total person-time. An at-risk period of 12 months after any dose will be used. | During the entire study period (From Month 0 up to Month 60) | 
| Occurrence of meningitis cases identified at site level (first line laboratory) | Number of cases of meningitis based on lab testing performed at site level. Meningitis cases identified at site level (first line laboratory assessment) in children <5 years old, living in the study area, prior to implementation of RTS,S/AS01E. | During the entire study period (From Month 0 up to Month 60) | 
| Occurrence of risk factors for AESI, other AE leading to hospitalisation or death, meningitis and malaria | Number of children <5 years old, included in active or enhanced hospitalisation surveillance, prior to implementation of RTS,S/AS01E with at least one risk. | During the entire study period (From Month 0 up to Month 60) | 
| Occurrences of causes of hospitalisation (including those attributed to an AESI, other AE, meningitis, or malaria) | Occurrence of hospitalisation assessed in children <5 years old, included in active or enhanced hospitalisation surveillance, prior to implementation of RTS,S/AS01E. | During the entire study period (From Month 0 up to Month 60) | 
| Number of deaths by cause (overall and by gender) | The number of deaths by cause is assessed in children <5 years old, included in active or enhanced hospitalisation surveillance, prior to implementation of RTS,S/AS01E.The analysis of death causes is classified by MedDRA and assessed overall and by gender. | During the entire study period (From Month 0 up to Month 60) | 
| Incidence of febrile convulsions following administration of routine EPI vaccines | Febrile convulsions are assessed in children <5 years old, included in active or enhanced hospitalisation surveillance, prior to implementation of RTS,S/AS01E. Febrile convulsions are defined as generalised seizures with measured fever greater than or equal to (≥) 37.5 degrees Celsius (°C) (axillary) or reported history of fever. Incidence rates will be calculated by dividing the number of subjects reporting at least one event over the follow-up period by the total person-time. Two at-risk periods will use: the 7-day period (Days 0-6) and the 1-month period (Days 0-29) following any vaccine administration. | During the entire study period (From Month 0 up to Month 60) | 
| Incidence of any malaria reported using rapid diagnostic test (RDT) and/or microscopy | The incidence of any malaria detected by RDT and/or microscopy is calculated by dividing the number of subjects reporting events over the follow-up period by the total person-time for children enrolled in active surveillance. Any malaria includes uncomplicated and severe cases, including cerebral malaria. Uncomplicated is defined as: Plasmodium parasitaemia greater than (>) 0 detected by microscopy and/or RDT, fever (temperature ≥ 37.5°C) and no signs of severity or evidence (clinical or laboratory) of vital organ dysfunction. Severe is defined as: P. falciparum parasitaemia > 0 detected by microscopy and/or RDT and one or more of the following: impaired consciousness, prostration, multiple convulsions, acidosis, hypoglycaemia, severe malarial anaemia, renal impairment, jaundice, pulmonary oedema, significant bleeding, shock, hyperparasitaemia. Cerebral malaria is defined as severe P. falciparum malaria with impaired consciousness. | During the entire study period (From Month 0 up to Month 60) | 
| Incidence of severe malaria reported using rapid diagnostic test (RDT) and/or microscopy | The incidence of severe malaria detected by RDT and/or microscopy is calculated by dividing the number of subjects reporting events over the follow-up period by the total person-time for children enrolled in the study. | During the entire study period (From Month 0 up to Month 60) | 
| Incidence of cerebral malaria reported using rapid diagnostic test (RDT) and/or microscopy | The incidence of cerebral malaria detected by RDT and/or microscopy will be calculated by dividing the number of subjects reporting events over the follow-up period by the total person-time for children enrolled in the study. | During the entire study period (From Month 0 up to Month 60) | 
| Prevalence of anaemia among hospitalised children | The prevalence for anaemia is computed by dividing the number of all cases by the number of enrolled children. All anaemia: haemoglobin <11 grams per deciliter (g/dL). Severe anaemia: haemoglobin <7g/dL. | During the entire study period (From Month 0 up to Month 60) | 
| Incidence of all-cause hospitalisations and hospitalisations attributed to malaria (including P. falciparum) | The hospitalisation cases are assessed in children <5 years old, included in active surveillance, prior to implementation of RTS,S/AS01E.The incidence of hospitalisation cases is calculated by dividing the number of children hospitalised during study period over the total person-time for children enrolled in active surveillance. Hospitalisation for malaria (including P. falciparum) is defined as: a hospitalised subject with malaria (including P. falciparum malaria) and for whom malaria is the primary cause of hospitalisation. | During the entire study period (From Month 0 up to Month 60) | 
| Mortality rate (all-cause mortality and deaths attributed to malaria [including P. falciparum]), overall and by gender | Mortality rate is calculated by dividing the number of deaths due to any cause or due to malaria over the total person-time for children enrolled in the study. | During the entire study period (From Month 0 up to Month 60) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Surveillance study, Adverse Events of Specific Interest (AESI), Children, Infants, Adverse events (AE) leading to hospitalisation or death, Meningitis, Epidemiology, Africa