| Protocol No: | ECCT/19/06/01 | Date of Protocol: | 11-10-2017 |
| Study Title: | A prospective study to evaluate the safety, effectiveness and impact of the RTS,S/AS01E vaccine in young children in sub-Saharan Africa. |
| Study Objectives: | Primary objectives • To estimate the incidence of protocol-defined potential adverse events of special interest (AESI), and of other adverse events (AE) leading to hospitalisation or death, in children vaccinated with of RTS,S/AS01E. • To estimate the incidence of aetiology-confirmed meningitis in children vaccinated with RTS,S/AS01E. Secondary objectives Safety In children enrolled in EPI-MAL-003 study (vaccinated with RTS,S/AS01E or not vaccinated with RTS,S/AS01E): • To estimate the incidence of aetiology-confirmed and/or probable meningitis (final classification). • To estimate the incidence of probable meningitis (final classification). • To estimate the incidence of aetiology-confirmed, probable and/or clinically suspected meningitis (final classification). • To estimate the incidence of cerebral malaria (malaria diagnosed by rapid diagnostic test [RDT] and/or microscopy). • To estimate the mortality rate (all-cause mortality and deaths attributed to malaria [including P. falciparum]), overall and by gender. • To describe risk factors for AESI, other AE leading to hospitalisation or death, meningitis, and malaria. • To describe the causes of hospitalisation (including AESI, other AE, meningitis and malaria). • To describe the causes of death, overall and by gender. • To assess the risk of febrile convulsions during the 7-day period and 1-month period following each dose of RTS,S/AS01E. In children enrolled in EPI-MAL-002 or EPI-MAL-003 studies (vaccinated with RTS,S/AS01E or not vaccinated with RTS,S/AS01E): • To monitor trends over time of meningitis cases identified at site level (first line laboratory). • To assess the potential association between vaccination and meningitis by comparing the incidence of aetiology-confirmed meningitis in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. • To assess the potential association between vaccination and meningitis by comparing the incidence of aetiology-confirmed and/or probable meningitis in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. • To assess the potential association between vaccination and meningitis by comparing the incidence of aetiology-confirmed, probable and/or clinically suspected meningitis in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. • To assess the potential association between vaccination and AESI, and other AE leading to hospitalisation or death by comparing the incidence of these events in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. • To assess the potential association between vaccination and cerebral malaria by comparing the incidence of these events in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. • To assess the potential association, overall and by gender, between vaccination and death by comparing the incidence of these events in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. Effectiveness and impact • To estimate the vaccine effectiveness (direct effect) and the impact (indirect, total and overall effects) of vaccination with RTS,S/AS01E on the incidence of any malaria (including P. falciparum malaria), severe malaria (including P. falciparum malaria) and cerebral malaria diagnosed by RDT and/or microscopy. • To estimate the vaccine effectiveness (direct effect) and impact (indirect, total and overall effects) of vaccination with RTS,S/AS01E on: o The prevalence of anaemia among hospitalised children. o The incidence of all-cause hospitalizations and hospitalizations attributed to malaria (including P. falciparum). o The mortality rate (all-cause mortality and deaths attributed to malaria [including P. falciparum]) overall and by gender. |
| 1 | Primary objectives • To estimate the incidence of protocol-defined potential adverse events of special interest (AESI), and of other adverse events (AE) leading to hospitalisation or death, in children vaccinated with of RTS,S/AS01E. • To estimate the incidence of aetiology-confirmed meningitis in children vaccinated with RTS,S/AS01E. Secondary objectives Safety In children enrolled in EPI-MAL-003 study (vaccinated with RTS,S/AS01E or not vaccinated with RTS,S/AS01E): • To estimate the incidence of aetiology-confirmed and/or probable meningitis (final classification). • To estimate the incidence of probable meningitis (final classification). • To estimate the incidence of aetiology-confirmed, probable and/or clinically suspected meningitis (final classification). • To estimate the incidence of cerebral malaria (malaria diagnosed by rapid diagnostic test [RDT] and/or microscopy). • To estimate the mortality rate (all-cause mortality and deaths attributed to malaria [including P. falciparum]), overall and by gender. • To describe risk factors for AESI, other AE leading to hospitalisation or death, meningitis, and malaria. • To describe the causes of hospitalisation (including AESI, other AE, meningitis and malaria). • To describe the causes of death, overall and by gender. • To assess the risk of febrile convulsions during the 7-day period and 1-month period following each dose of RTS,S/AS01E. In children enrolled in EPI-MAL-002 or EPI-MAL-003 studies (vaccinated with RTS,S/AS01E or not vaccinated with RTS,S/AS01E): • To monitor trends over time of meningitis cases identified at site level (first line laboratory). • To assess the potential association between vaccination and meningitis by comparing the incidence of aetiology-confirmed meningitis in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. • To assess the potential association between vaccination and meningitis by comparing the incidence of aetiology-confirmed and/or probable meningitis in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. • To assess the potential association between vaccination and meningitis by comparing the incidence of aetiology-confirmed, probable and/or clinically suspected meningitis in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. • To assess the potential association between vaccination and AESI, and other AE leading to hospitalisation or death by comparing the incidence of these events in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. • To assess the potential association between vaccination and cerebral malaria by comparing the incidence of these events in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. • To assess the potential association, overall and by gender, between vaccination and death by comparing the incidence of these events in children vaccinated with RTS,S/AS01E with the incidence of these events in children not vaccinated with RTS,S/AS01E. Effectiveness and impact • To estimate the vaccine effectiveness (direct effect) and the impact (indirect, total and overall effects) of vaccination with RTS,S/AS01E on the incidence of any malaria (including P. falciparum malaria), severe malaria (including P. falciparum malaria) and cerebral malaria diagnosed by RDT and/or microscopy. • To estimate the vaccine effectiveness (direct effect) and impact (indirect, total and overall effects) of vaccination with RTS,S/AS01E on: o The prevalence of anaemia among hospitalised children. o The incidence of all-cause hospitalizations and hospitalizations attributed to malaria (including P. falciparum). o The mortality rate (all-cause mortality and deaths attributed to malaria [including P. falciparum]) overall and by gender. |
| Laymans Summary: | GlaxoSmithKline (GSK) Biologicals has developed a malaria vaccine, RTS,S/AS01E, for routine immunisation of children living in malaria-endemic countries of sub-Saharan Africa (SSA). RTS,S/AS01E is the first vaccine to be implemented for the prevention of malaria in the paediatric population. The World Health Organization (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 SSA countries, administering 3 doses of the vaccine to children 5-9 months of age in areas of moderate to- high transmission of malaria with a fourth dose administered 15-18 months following the third dose. 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 a WHO-coordinated pilot implementation programme, referred to as the Malaria Vaccine Implementation Programme (MVIP). 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. Sites from Ghana and Kenya that were part of study EPI-MAL-002 should become study sites in EPIMAL- 003 which will be exposed clusters. The safety and efficacy of RTS,S/AS01E have been evaluated during pre-authorisation clinical trials conducted mainly in SSA. Study EPI-MALARIA-003 VS AME (115056) will further evaluate the safety, effectiveness and impact of the vaccine during initial implementation. A pre-implementation (i.e. before vaccine implementation) surveillance study, EPI-MALARIA-002 VS AME (115055) will measure the baseline incidence of protocol-defined adverse events of special interest (AESI), other adverse events (AE) leading to hospitalisation or death, meningitis, malaria morbidity and mortality. The mortality rate, overall and by gender, are also being estimated. EPI-MAL-003 is intended primarily as a post-implementation safety study, together with vaccine effectiveness and impact estimations. In parallel with both EPI-MAL-002 and EPI-MAL-003, a third study (EPI-MALARIA-005 BOD AME [116682] is conducted to measure malaria transmission intensity and other malaria control interventions as confounding factors in the study site areas. The three studies will be conducted in similar if not identical settings. A strong capacity development component is included in the baseline study EPIMAL-002. The study staff (e.g. health care/field worker) will visit the study participant at home or at the local health care facility up to 11 times during the study. Each of these planned study visits should take about 1 hour. If the child takes part in the study and if he/she is found to be unwell at any of the study visits (visits 1 to 9), he/she will be referred to a health care facility and treated under existing Kenya Ministry of Health services/programs. If the medical problem cannot be treated at home or at the nearest health care facility, he/she will be referred to a hospital. If this were to happen, transport will be arranged for this visit to see the doctor. The participant will benefit from regular check-up and advice during the planned visits. |
| 1 | GlaxoSmithKline (GSK) Biologicals has developed a malaria vaccine, RTS,S/AS01E, for routine immunisation of children living in malaria-endemic countries of sub-Saharan Africa (SSA). RTS,S/AS01E is the first vaccine to be implemented for the prevention of malaria in the paediatric population. The World Health Organization (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 SSA countries, administering 3 doses of the vaccine to children 5-9 months of age in areas of moderate to- high transmission of malaria with a fourth dose administered 15-18 months following the third dose. 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 a WHO-coordinated pilot implementation programme, referred to as the Malaria Vaccine Implementation Programme (MVIP). 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. Sites from Ghana and Kenya that were part of study EPI-MAL-002 should become study sites in EPIMAL- 003 which will be exposed clusters. The safety and efficacy of RTS,S/AS01E have been evaluated during pre-authorisation clinical trials conducted mainly in SSA. Study EPI-MALARIA-003 VS AME (115056) will further evaluate the safety, effectiveness and impact of the vaccine during initial implementation. A pre-implementation (i.e. before vaccine implementation) surveillance study, EPI-MALARIA-002 VS AME (115055) will measure the baseline incidence of protocol-defined adverse events of special interest (AESI), other adverse events (AE) leading to hospitalisation or death, meningitis, malaria morbidity and mortality. The mortality rate, overall and by gender, are also being estimated. EPI-MAL-003 is intended primarily as a post-implementation safety study, together with vaccine effectiveness and impact estimations. In parallel with both EPI-MAL-002 and EPI-MAL-003, a third study (EPI-MALARIA-005 BOD AME [116682] is conducted to measure malaria transmission intensity and other malaria control interventions as confounding factors in the study site areas. The three studies will be conducted in similar if not identical settings. A strong capacity development component is included in the baseline study EPIMAL-002. The study staff (e.g. health care/field worker) will visit the study participant at home or at the local health care facility up to 11 times during the study. Each of these planned study visits should take about 1 hour. If the child takes part in the study and if he/she is found to be unwell at any of the study visits (visits 1 to 9), he/she will be referred to a health care facility and treated under existing Kenya Ministry of Health services/programs. If the medical problem cannot be treated at home or at the nearest health care facility, he/she will be referred to a hospital. If this were to happen, transport will be arranged for this visit to see the doctor. The participant will benefit from regular check-up and advice during the planned visits. |
| Abstract of Study: | This is an epidemiology study that intends to evaluate the safety, effectiveness and impact of the RTS,S/AS01E vaccine in young children in sub-Saharan Africa. GlaxoSmithKline (GSK) Biologicals has developed a pre-erythrocytic Plasmodium (P.) falciparum malaria vaccine, RTS,S/AS01E, for routine immunisation of children living in malaria-endemic countries of sub-Saharan Africa (SSA). The World Health Organization (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 SSA countries, administering 3 doses of the vaccine to children 5-9 months of age in areas of moderate to-high transmission of malaria with a fourth dose administered 15-18 months following the third dose. 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) in 2018 through a WHO-coordinated pilot implementation programme, referred to as the Malaria Vaccine Implementation Programme (MVIP). 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. Sites from these 3 countries that were part of study EPI-MAL-002 will become study sites in EPI-MAL-003 (EPI-MALARIA-003 VS AME (115056)) which will be exposed clusters. EPI-MAL-003 is a post-implementation study that will further evaluate the safety, effectiveness and impact of the vaccine during initial implementation. |