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

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• The term "passive surveillance" has been replaced by the term "enhanced hospitalisation surveillance".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.