Clinical trial NCT05041556: Strengthening the Evidence for Policy on the RTS,S/AS01 Malaria Vaccine
Official title: Strengthening the Evidence for Policy on the RTS,S/AS01 Malaria Vaccine: Assessment of Safety and Effectiveness Using Case-control Studies Embedded in the Malaria Vaccine Pilot Evaluation
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Malaria
Keywords: Malaria
Vaccines
Case-control
Safety
Mortality
Lead sponsor: Kintampo Health Research Centre, Ghana
Sponsor class: OTHER
Collaborators: name: European Vaccine Initiative
name: London School of Hygiene and Tropical Medicine
name: African Research Collaboration for Health Limited
name: Kenya Medical Research Institute
name: University of Malawi
name: PATH
First posted: 2021-09-13
Enrollment: 9280
Sex: ALL
Minimum age (years): 6
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will comprise children aged 6-59 months who live in RTS,S implementation areas in Ghana, Kenya and Malawi and who were eligible to have received RTS,S based on their date or birth and age

Brief summary: The ongoing Malaria Vaccine Pilot Evaluation (MVPE) is being conducted in Ghana, Malawi and Kenya through community and sentinel hospital surveillance systems and a series of household surveys (to measure vaccine coverage). The Malaria Vaccine Pilot Evaluation-Case Control (MVPE-CC) registered here as observational study is embedded within MVPE comprising case-control studies of clinical and mortality outcomes. Each case will require four controls, and caregiver informed consent will be required prior to study activities.

These observational case control studies will measure as complementary information to what is being collected through MVPE:

1. Safety among children who received the malaria vaccine, with focus on cerebral malaria, meningitis and severe malaria
2. The impact of the malaria vaccine on all-cause mortality for boys and girls, AND
3. Promote use of case-control approaches by Expanded Programmes on Immunization (EPI) and malaria control programmes.

Detailed description: Strengthening the evidence for policy on the RTS,S/AS01 malaria vaccine: assessment of safety and effectiveness using case-control studies embedded in the Malaria Vaccine Pilot Evaluation (MVPE). This project will support the embedding of case-control studies into the ongoing evaluation component of the RTS,S malaria vaccine pilot implementation programme (MVIP) in Ghana, Kenya, and Malawi. The evaluation data are being collected through a series of household surveys, and sentinel hospital and community mortality surveillance build on routine systems.

The case-control studies will run for a period of 45 months in the three countries (Ghana, Kenya, Malawi). The primary objectives of the case-control studies focus on safety, impact and capacity building. There will be no defined number of cases per country. Data for the case-control studies will be collected using two-pronged approach.

CASE-CONTROL STUDY OF CLINICAL OUTCOMES.

For each case, 4 controls will be recruited.

Children living in the study area of the ongoing MVPE and recruited from the catchment areas of the sentinel hospital of the MVPE will be recruited. Children aged 6 months - 59 months will be recruited into the study. All eligible cases identified from the MVPE sentinel hospital surveillance systems will be recruited. Data needed on cases already being collected as part of the MVPE sentinel surveillance will be updated following consent. Eligible cases will be approached for consent for the case-control component and to ascertain their residence and collect additional data. Neighbourhood controls will be recruited by canvassing homes in a predetermined pattern from the case's home until four eligible controls are identified and interviewed. Research officers will identify and consent controls. Similar information will be collected as for the cases. A total of 46 meningitis cases and 184 controls, and 930 severe malaria cases and 3720 controls will contribute to the clinical case-control endpoints across the three countries. This is expected to provide 90% power to detect a 10 to 5-fold increase in incidence of meningitis in vaccine recipients. The updated power calculations indicate about 600 severe malaria cases is needed to detect the 40% benefit that was seen in the phase 3 trial. And 330 severe malaria cases eligible to have received 3 doses (and not yet eligible for dose 4) are needed for 80% power to detect a 30% reduction in incidence. A total of 180 cases of cerebral malaria and 720 controls are expected to be recruited to provide 90% power to detect a 2-fold increase in incidence of cerebral malaria in children who received 3 doses of RTSS/AS01

CASE-CONTROL STUDY OF MORTALITY OUTCOMES.

For each case, 4 controls will be recruited.

As part of the MVPE, data is already captured on all children aged 1 - 59 months who live in an MVIP area and die by verbal autopsy teams at the child's home. Data already collected within the context of the MVPE will be merged to the case-control dataset using the child's unique identifier, rather than duplicated. For the mortality case-control outcomes, verbal autopsy teams will identify eligible deaths at the time of the verbal autopsy. Written, or witnessed and thumb-printed, informed consent will be obtained from each child's carer before data are included in the case-control dataset. Data may be captured retrospectively once the informed consent form is signed or thumb-printed.

Four controls will be selected per case, and matched based on their location and their age (within 30 days of the case's date of birth). To avoid selection bias, research officers will canvass up to several homes in a predetermined pattern from the case's home until four controls are identified and interviewed. All eligible controls will be approached for consent. The same information will be collected for controls as for the cases. A total of 1000 mortality cases and 4000 controls will contribute to the clinical case-control endpoints. This is expected to provide 90% power to detect a 2-fold difference between girls and boys.

Eligibility criteria: Inclusion Criteria:

* Willingness to participate in study evidenced by written informed consent provided by an adult caregiver
* Resident in an RTS,S/AS01 implementation area within the catchment area of MVPE sentinel hospitals
* Eligible, based on date of birth and age, to have received RTSS/AS01
* Meets the case or control definitions above.

Exclusion Criteria:

* Caregiver not willing to provide consent

Primary outcomes:
measure: Number of children admitted with a diagnosis of probable and confirmed meningitis
timeFrame: Through study completion, an average of 1 year
measure: Number of children admitted with a diagnosis of severe malaria
timeFrame: Through study completion, an average of 1 year
measure: The number of deaths of any cause
timeFrame: Through study completion, an average of 1 year
measure: Number of deaths in children by gender
timeFrame: Through study completion, an average of 1 year
Secondary outcomes:
measure: Number of children with a diagnosis of severe malaria in relation to the 4th dose of RTS,S
timeFrame: Through study completion, an average of 1 year
measure: Number of children with a diagnosis of cerebral malaria in relation to the 4th dose of RTS,S
timeFrame: Through study completion, an average of 1 year
measure: Number of deaths of any cause in relation to the 4th dose of RTS,S
timeFrame: Through study completion, an average of 1 year
measure: Number of deaths among girls in relation to the 4th dose of RTS,S
timeFrame: Through study completion, an average of 1 year
Other outcomes:
Locations:
city: Kintampo
country: Ghana
facility: Kintampo Health Research Centre
city: Nairobi
country: Kenya
facility: African Research Collaboration for Health Limited
city: Nairobi
country: Kenya
facility: Kenya Medical Research Institute (KEMRI)
city: Blantyre
country: Malawi
facility: College of Medicine, University of Malawi
Study officials:
affiliation: Kintampo Health Research Centre, Ghana
name: Kwaku Poku Asante, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: College of Medicine, University of Malawi, Malawi
name: Don Mathanga, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: African Research Collaboration for Health Limited, Kenya
name: Samuel Akech, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kenya Medical Research Institute
name: Simon Kariuki, PhD
role: PRINCIPAL_INVESTIGATOR
References: