<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03806465</url>
  </required_header>
  <id_info>
    <org_study_id>RTSS MVPE</org_study_id>
    <nct_id>NCT03806465</nct_id>
  </id_info>
  <brief_title>Malaria Vaccine Pilot Evaluation</brief_title>
  <acronym>MVPE</acronym>
  <official_title>An Evaluation of the Pilot Implementation of RTS,S/AS01 Through Routine Health Systems in Moderate to High Malaria Transmission Settings in Africa</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>World Health Organization</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>World Health Organization</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The RTS,S/AS01 malaria vaccine is being introduced sub-nationally in phased pilot&#xD;
      introductions through the EPI programmes in Malawi Ghana and Kenya. Vaccine introduction is&#xD;
      by the respective MoH in selected areas randomly assigned to receive the vaccine at the&#xD;
      beginning of the pilots. In the context of this programmatic activity, the Malaria Vaccine&#xD;
      Pilot Evaluation (MVPE) registered here as observational evaluations during early vaccine&#xD;
      introduction, include a series of 3 household surveys, and sentinel hospital and community&#xD;
      mortality surveillance, building on routine systems.&#xD;
&#xD;
      These observational evaluations will measure:&#xD;
&#xD;
        1. The programmatic feasibility of delivering a 4 dose schedule;&#xD;
&#xD;
        2. Safety in routine use, with focus on cerebral malaria and meningitis;&#xD;
&#xD;
        3. The impact of the malaria vaccine in routine use on severe malaria and all-cause&#xD;
           mortality&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      An evaluation of the pilot implementation of RTS,S/AS01 through routine health systems in&#xD;
      moderate to high malaria transmission settings in Ghana, Kenya and Malawi. In the context of&#xD;
      the new vaccine introduction, the Ministries of Health in the three countries will introduce&#xD;
      the malaria vaccine (RTS,S/AS01) in a phased fashion (with some areas introducing the malaria&#xD;
      vaccine first and the latter half, after the evaluation period) building on the national&#xD;
      immunization programmes which routinely deliver vaccines and expanding the schedule of their&#xD;
      routine EPI contacts.&#xD;
&#xD;
      The evaluation of the pilot implementation will run for a total of about 46 months in each&#xD;
      country. This will focus on the three main primary objectives of feasibility, safety and&#xD;
      impact. The pilot implementation assumes that a total of 46-60 clusters will be identified&#xD;
      per country, evenly split between implementation and comparison areas, with each cluster&#xD;
      contributing approximately 4,000 children per year to the evaluation of RTS,S/AS01. Hence a&#xD;
      total of approximately 120,000 children will receive the RTS,S vaccine in each country in&#xD;
      each year. Evaluation data will be collected in the following ways.&#xD;
&#xD;
      COMMUNITY BASED MORTALITY SURVEILLANCE&#xD;
&#xD;
      Community based mortality surveillance will be established across the pilot evaluation areas&#xD;
      to enable the evaluation of the impact of the malaria vaccine on all-cause mortality. This&#xD;
      will use a network of Village Reporters (VR) to document all deaths among children aged up to&#xD;
      48 months in the implementation and comparison areas. Once the death is notified, a&#xD;
      standardized, WHO-approved Verbal Autopsy (VA) will be performed, according to WHO guidelines&#xD;
      and locally acceptable practices. The VA will focus is on confirming death, age and&#xD;
      vaccination status. The total number of clusters per country is expected to range from 46-60.&#xD;
      Assuming 4,000 children born per cluster per year, 30 months of vaccination and a total&#xD;
      follow-up of 44 months, each cluster will contribute 23,134 person years at risk (pyar),&#xD;
      allowing for 1% mortality in the first month of life, and 0.08% mortality for every month&#xD;
      after the first month. This equates to a mortality risk of 22.2 per 1000 for children aged 5&#xD;
      to 36 months. A mortality risk of 21 per 1,000 equates to a rate, over 2.5 years, of 8.489455&#xD;
      per 1,000 pyar. Based on a minimum mortality rate of 8.5 per 1000 pyar, 23 clusters in each&#xD;
      arm, each with an annual birth cohort of approximately 4,000 subjects, would have 80% power&#xD;
      to detect, at the 5% significance level, a decrease of at least 10% in overall mortality in&#xD;
      each country.&#xD;
&#xD;
      With this mortality risk, the pilot evaluation it is estimated to have approximately 80%&#xD;
      power to detect an interaction between gender and treatment of 1.15 (i.e an increased risk of&#xD;
      mortality in girls of 1.035), compared with the 1.9-fold increase in risk among girls&#xD;
      receiving RTS,S/AS01 in the RTS,S Phase 3 trial.&#xD;
&#xD;
      FEASIBILITY (CROSS SECTIONAL HOUSEHOLD) SURVEYS)&#xD;
&#xD;
      Three household surveys will be conducted to evaluate the programmatic feasibility to deliver&#xD;
      a 4 dose schedule at baseline (before vaccination starts), 18 months and 30 months after&#xD;
      start of vaccination.&#xD;
&#xD;
      A sample size of 100 houses per cluster will estimate the cluster-specific coverage of&#xD;
      RTS,S/AS01 to within 10% (ie 95% CI from 40 to 60%) using a conservative estimate of 50%&#xD;
      coverage and a high response rate above 95% in each cluster. Assuming a design effect of 1.5&#xD;
      between clusters, the overall precision in RTS,S/AS01 and coverage estimates of other&#xD;
      vaccines over the pilot programme's implementation and comparison areas will be 2% (ie 95%CI&#xD;
      48% to 52%) in each country. This will result in 15,800 (6,600 in Ghana, 4,600 each in Kenya&#xD;
      and Malawi) households included in the surveys. The second household survey may be powered to&#xD;
      generate coverage estimates in each arm, rather than in each cluster, to within ±2% of the&#xD;
      true value.&#xD;
&#xD;
      SENTINEL HOSPITAL SURVEILLANCE&#xD;
&#xD;
      Four to eight sentinel hospitals will be identified in each country to collect information on&#xD;
      a larger scale on the safety of the malaria vaccine in children aged less than 5 years&#xD;
      admitted with a focus on cases of cerebral malaria and meningitis. The catchment area of each&#xD;
      hospital (approximately a cluster) is expected to have an annual birth cohort of, and provide&#xD;
      services for, approximately 4,000 children in the MVPE. Hence a total catchment area of&#xD;
      48,000 children in implementation areas and another 48,000 children in comparison areas will&#xD;
      contribute to the hospital-based evaluation of safety across the programme (three countries,&#xD;
      Ghana, Kenya and Malawi). This is expected to provide 80% power to detect a 1.7-fold increase&#xD;
      in risk of cerebral malaria and 2.6-fold increase in risk of meningitis. Children admitted to&#xD;
      the sentinel hospitals in this age group will be assessed for severe malaria and meningitis&#xD;
      using a standardised surveillance approach.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 25, 2019</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">June 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>The number of deaths of any cause</measure>
    <time_frame>From 0 to 46 months after vaccination starts</time_frame>
    <description>Number of deaths of any cause in children aged 1-59 months.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of children admitted with a diagnosis of probable and confirmed meningitis cases</measure>
    <time_frame>From 0 to 30 months after vaccination starts</time_frame>
    <description>Number of children with probable and confirmed meningitis A probable case if in a suspected case, the macroscopic aspect of the CSF is turbid, cloudy or purulent; or the CSF leukocyte count is &gt;10 cells/mm3. A confirmed case is if a suspected or probable case is laboratory confirmed by culturing or identifying (i.e. by polymerase chain reaction, immunochromatographic dipstick or latex agglutination) bacterial, viral or other aetiology in the CSF.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of children admitted with a diagnosis of cerebral malaria</measure>
    <time_frame>From 0 to 30 months after vaccination starts</time_frame>
    <description>Cerebral malaria is defined as Severe P. falciparum malaria with coma (Glasgow coma score &lt; 11 in children two years of age or older [≥ 2 years] or Blantyre coma score &lt; 3 in children less than two years of age [(&lt; 2 years]); and If malaria with seizure: coma persisting for &gt; 30 min after the seizure. Other treatable causes of coma should be excluded before diagnosing cerebral malaria (e.g. hypoglycaemia, bacterial meningitis)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of children aged 12-23 months who have completed the primary series (the 3 dose regime) of the malaria vaccine</measure>
    <time_frame>At 18 months after vaccination starts</time_frame>
    <description>Prevalence of children aged 12-23 months who had completed three doses of RTS,S/AS01 at the second household survey</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of children aged 27-38 months who have completed the 4th dose of the malaria vaccine</measure>
    <time_frame>At 30 months after vaccination starts</time_frame>
    <description>Prevalence of children aged 27-38 months who had completed four doses of RTS,S/AS01 at the third household survey</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of deaths in children by gender</measure>
    <time_frame>From 0 to 46 months after vaccination starts</time_frame>
    <description>Number of deaths in children stratified by gender in children aged 1-59 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of deaths in hospitalised children by gender</measure>
    <time_frame>From 0 to 46 months after vaccination starts</time_frame>
    <description>Number of deaths in hospitalized children stratified by gender in children aged 1-59 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of malaria associated deaths in hospitalised children by gender</measure>
    <time_frame>From 0 to 46 months after vaccination starts</time_frame>
    <description>Number of malaria specific deaths stratified by gender in hospitalized children aged 1-59 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children with a diagnosis of severe malaria</measure>
    <time_frame>From 0 to 30 months after vaccination starts</time_frame>
    <description>Hospital admissions with malaria which meet WHO criteria for a diagnosis of severe malaria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of deaths excluding those attributed to trauma, poisoning and drowning</measure>
    <time_frame>From 0 to 46 months after vaccination starts</time_frame>
    <description>Number of non traumatic deaths in children aged 1-59 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children with a diagnosis of aetiology confirmed meningitis</measure>
    <time_frame>30 months after vaccination starts</time_frame>
    <description>Number of hospital admissions which meet WHO criteria for a diagnosis of aetiologically confirmed meningitis admitted to sentinel hospitals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children with a diagnosis of suspected meningitis</measure>
    <time_frame>From 0 to 30 months after vaccination starts</time_frame>
    <description>Number of hospital admissions which meet WHO criteria for a diagnosis of suspected meningitis admitted to sentinel hospitals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children with a diagnosis of probable meningitis</measure>
    <time_frame>From 0 to 30 months after vaccination starts</time_frame>
    <description>Number of hospital admissions which meet WHO criteria for a diagnosis of probable meningitis admitted to sentinel hospitals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children with a diagnosis of malaria</measure>
    <time_frame>From 0 to 30 months after vaccination starts</time_frame>
    <description>Number of hospital admissions which meet WHO criteria for a diagnosis of malaria admitted to sentinel hospitals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children with a non-malaria diagnosis</measure>
    <time_frame>From 0 to 30 months after vaccination starts</time_frame>
    <description>Number of hospital admissions which do not meet WHO criteria for a diagnosis of malaria admitted to sentinel hospitals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children with a diagnosis of anaemia</measure>
    <time_frame>From 0 to 30 months after vaccination starts</time_frame>
    <description>Number of hospital admissions which meet WHO criteria for a diagnosis of anaemia admitted to sentinel hospitals . Anaemia is haemoglobin less than 11g/dL.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children who have received all their routine EPI vaccines as recommended by their national immunization schedule</measure>
    <time_frame>At 18 and 30 months after vaccination starts</time_frame>
    <description>Routine EPI vaccines include all doses of OPV, pentavalent, rotavirus, pneumococcal and measles vaccines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children who have received all the recommended malaria prevention and control measures</measure>
    <time_frame>At 18 and 30 months after vaccination starts</time_frame>
    <description>Recommended malaria prevention and control measures include insecticide treated bed nets, IPTi and indoor residual spraying.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of children who have received all of the other key childhood interventions</measure>
    <time_frame>At 18 and 30 months after vaccination starts</time_frame>
    <description>Other key childhood interventions include anti-helminth administration (deworming) and Vitamin A supplementation</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">15800</enrollment>
  <condition>Malaria,Falciparum</condition>
  <condition>Feasibility</condition>
  <condition>Safety</condition>
  <condition>Mortality</condition>
  <arm_group>
    <arm_group_label>Feasibility survey</arm_group_label>
    <description>These will be children living in the vaccinating and in non-vaccinating areas aged less than 5 years of age. For the midline household survey, this would be restricted to children aged 12-23 months of age.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sentinel hospital surveillance</arm_group_label>
    <description>These will be children living in the vaccinating and in non-vaccinating areas aged less than 5 years of age who are hospitalized in the 18 sentinel hospitals.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Community mortality surveillance</arm_group_label>
    <description>These will be children whose deaths are reported in the vaccinating and in non-vaccinating areas aged less than 5 years of age .</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Feasibility survey</intervention_name>
    <description>A survey questionnaire will be administered at each household. At the baseline household survey, each child aged less than 5 years will be tested for malaria using a rapid malaria test.</description>
    <arm_group_label>Feasibility survey</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Sentinel hospital surveillance</intervention_name>
    <description>Cerebrospinal samples will be collected from all children hospitalised and suspected of having meningitis.</description>
    <arm_group_label>Sentinel hospital surveillance</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Community mortality surveillance</intervention_name>
    <description>A verbal autopsy will be performed</description>
    <arm_group_label>Community mortality surveillance</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Cerebrospinal fluid&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The study population will comprise children aged 1-59 months living in the areas&#xD;
        geographically-defined for this evaluation of the RTS,S/AS01 Malaria Vaccine Implementation&#xD;
        in three countries (Ghana, Kenya and Malawi) in sub-Saharan Africa.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Children aged 1-59 months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Children aged less than 1 month or greater than 59 months&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>59 Months</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Don Mathanga, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>College of Medicine, Malawi</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kwaku Poku Asante, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kintampo Health Research Centre, Ghana</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Aaron Samuels, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>CDC-Kenya Malaria Program</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kintampo Health Research Centre</name>
      <address>
        <city>Kintampo</city>
        <country>Ghana</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CDC Kenya Malaria Programme</name>
      <address>
        <city>Kisumu</city>
        <country>Kenya</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>College of Medicine</name>
      <address>
        <city>Blantyre</city>
        <country>Malawi</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Ghana</country>
    <country>Kenya</country>
    <country>Malawi</country>
  </location_countries>
  <link>
    <url>https://www.who.int/docs/default-source/immunization/mvip/mvip-milestones-to-programme-development-final.pdf?Status=Temp&amp;sfvrsn=14768db0_2</url>
    <description>Key milestones in the development of the Malaria Vaccine Implementation Programme (MVIP): from pilot recommendation to vaccine introduction</description>
  </link>
  <reference>
    <citation>Malaria vaccine: WHO position paper-January 2016. Wkly Epidemiol Rec. 2016 Jan 4;91(4):33-51. No abstract available. English, French.</citation>
    <PMID>26829826</PMID>
  </reference>
  <reference>
    <citation>RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015 Jul 4;386(9988):31-45. doi: 10.1016/S0140-6736(15)60721-8. Epub 2015 Apr 23. Erratum In: Lancet. 2015 Jul 4;386(9988):30.</citation>
    <PMID>25913272</PMID>
  </reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>December 14, 2018</study_first_submitted>
  <study_first_submitted_qc>January 15, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 16, 2019</study_first_posted>
  <last_update_submitted>August 6, 2021</last_update_submitted>
  <last_update_submitted_qc>August 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 13, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>World Health Organization</investigator_affiliation>
    <investigator_full_name>Patricia Njuguna</investigator_full_name>
    <investigator_title>Medical Officer</investigator_title>
  </responsible_party>
  <keyword>Vaccine</keyword>
  <keyword>Malaria</keyword>
  <keyword>Africa</keyword>
  <keyword>Child</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malaria</mesh_term>
    <mesh_term>Malaria, Falciparum</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 22, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/65/NCT03806465/Prot_ICF_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 28, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/65/NCT03806465/SAP_002.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03806465
org study id: RTSS MVPE
nct id: NCT03806465
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The RTS,S/AS01 malaria vaccine is being introduced sub-nationally in phased pilot
      introductions through the EPI programmes in Malawi Ghana and Kenya. Vaccine introduction is
      by the respective MoH in selected areas randomly assigned to receive the vaccine at the
      beginning of the pilots. In the context of this programmatic activity, the Malaria Vaccine
      Pilot Evaluation (MVPE) registered here as observational evaluations during early vaccine
      introduction, include a series of 3 household surveys, and sentinel hospital and community
      mortality surveillance, building on routine systems.

      These observational evaluations will measure:

        1. The programmatic feasibility of delivering a 4 dose schedule;

        2. Safety in routine use, with focus on cerebral malaria and meningitis;

        3. The impact of the malaria vaccine in routine use on severe malaria and all-cause
           mortality
An evaluation of the pilot implementation of RTS,S/AS01 through routine health systems in
      moderate to high malaria transmission settings in Ghana, Kenya and Malawi. In the context of
      the new vaccine introduction, the Ministries of Health in the three countries will introduce
      the malaria vaccine (RTS,S/AS01) in a phased fashion (with some areas introducing the malaria
      vaccine first and the latter half, after the evaluation period) building on the national
      immunization programmes which routinely deliver vaccines and expanding the schedule of their
      routine EPI contacts.

      The evaluation of the pilot implementation will run for a total of about 46 months in each
      country. This will focus on the three main primary objectives of feasibility, safety and
      impact. The pilot implementation assumes that a total of 46-60 clusters will be identified
      per country, evenly split between implementation and comparison areas, with each cluster
      contributing approximately 4,000 children per year to the evaluation of RTS,S/AS01. Hence a
      total of approximately 120,000 children will receive the RTS,S vaccine in each country in
      each year. Evaluation data will be collected in the following ways.

      COMMUNITY BASED MORTALITY SURVEILLANCE

      Community based mortality surveillance will be established across the pilot evaluation areas
      to enable the evaluation of the impact of the malaria vaccine on all-cause mortality. This
      will use a network of Village Reporters (VR) to document all deaths among children aged up to
      48 months in the implementation and comparison areas. Once the death is notified, a
      standardized, WHO-approved Verbal Autopsy (VA) will be performed, according to WHO guidelines
      and locally acceptable practices. The VA will focus is on confirming death, age and
      vaccination status. The total number of clusters per country is expected to range from 46-60.
      Assuming 4,000 children born per cluster per year, 30 months of vaccination and a total
      follow-up of 44 months, each cluster will contribute 23,134 person years at risk (pyar),
      allowing for 1% mortality in the first month of life, and 0.08% mortality for every month
      after the first month. This equates to a mortality risk of 22.2 per 1000 for children aged 5
      to 36 months. A mortality risk of 21 per 1,000 equates to a rate, over 2.5 years, of 8.489455
      per 1,000 pyar. Based on a minimum mortality rate of 8.5 per 1000 pyar, 23 clusters in each
      arm, each with an annual birth cohort of approximately 4,000 subjects, would have 80% power
      to detect, at the 5% significance level, a decrease of at least 10% in overall mortality in
      each country.

      With this mortality risk, the pilot evaluation it is estimated to have approximately 80%
      power to detect an interaction between gender and treatment of 1.15 (i.e an increased risk of
      mortality in girls of 1.035), compared with the 1.9-fold increase in risk among girls
      receiving RTS,S/AS01 in the RTS,S Phase 3 trial.

      FEASIBILITY (CROSS SECTIONAL HOUSEHOLD) SURVEYS)

      Three household surveys will be conducted to evaluate the programmatic feasibility to deliver
      a 4 dose schedule at baseline (before vaccination starts), 18 months and 30 months after
      start of vaccination.

      A sample size of 100 houses per cluster will estimate the cluster-specific coverage of
      RTS,S/AS01 to within 10% (ie 95% CI from 40 to 60%) using a conservative estimate of 50%
      coverage and a high response rate above 95% in each cluster. Assuming a design effect of 1.5
      between clusters, the overall precision in RTS,S/AS01 and coverage estimates of other
      vaccines over the pilot programme's implementation and comparison areas will be 2% (ie 95%CI
      48% to 52%) in each country. This will result in 15,800 (6,600 in Ghana, 4,600 each in Kenya
      and Malawi) households included in the surveys. The second household survey may be powered to
      generate coverage estimates in each arm, rather than in each cluster, to within ±2% of the
      true value.

      SENTINEL HOSPITAL SURVEILLANCE

      Four to eight sentinel hospitals will be identified in each country to collect information on
      a larger scale on the safety of the malaria vaccine in children aged less than 5 years
      admitted with a focus on cases of cerebral malaria and meningitis. The catchment area of each
      hospital (approximately a cluster) is expected to have an annual birth cohort of, and provide
      services for, approximately 4,000 children in the MVPE. Hence a total catchment area of
      48,000 children in implementation areas and another 48,000 children in comparison areas will
      contribute to the hospital-based evaluation of safety across the programme (three countries,
      Ghana, Kenya and Malawi). This is expected to provide 80% power to detect a 1.7-fold increase
      in risk of cerebral malaria and 2.6-fold increase in risk of meningitis. Children admitted to
      the sentinel hospitals in this age group will be assessed for severe malaria and meningitis
      using a standardised surveillance approach.
observational model: Other
time perspective: Prospective
measure: The number of deaths of any cause
time frame: From 0 to 46 months after vaccination starts
description: Number of deaths of any cause in children aged 1-59 months.
measure: Number of children admitted with a diagnosis of probable and confirmed meningitis cases
time frame: From 0 to 30 months after vaccination starts
description: Number of children with probable and confirmed meningitis A probable case if in a suspected case, the macroscopic aspect of the CSF is turbid, cloudy or purulent; or the CSF leukocyte count is >10 cells/mm3. A confirmed case is if a suspected or probable case is laboratory confirmed by culturing or identifying (i.e. by polymerase chain reaction, immunochromatographic dipstick or latex agglutination) bacterial, viral or other aetiology in the CSF.
measure: Number of children admitted with a diagnosis of cerebral malaria
time frame: From 0 to 30 months after vaccination starts
description: Cerebral malaria is defined as Severe P. falciparum malaria with coma (Glasgow coma score < 11 in children two years of age or older [≥ 2 years] or Blantyre coma score < 3 in children less than two years of age [(< 2 years]); and If malaria with seizure: coma persisting for > 30 min after the seizure. Other treatable causes of coma should be excluded before diagnosing cerebral malaria (e.g. hypoglycaemia, bacterial meningitis)
measure: Number of children aged 12-23 months who have completed the primary series (the 3 dose regime) of the malaria vaccine
time frame: At 18 months after vaccination starts
description: Prevalence of children aged 12-23 months who had completed three doses of RTS,S/AS01 at the second household survey
measure: Number of children aged 27-38 months who have completed the 4th dose of the malaria vaccine
time frame: At 30 months after vaccination starts
description: Prevalence of children aged 27-38 months who had completed four doses of RTS,S/AS01 at the third household survey
measure: Number of deaths in children by gender
time frame: From 0 to 46 months after vaccination starts
description: Number of deaths in children stratified by gender in children aged 1-59 months
measure: Number of deaths in hospitalised children by gender
time frame: From 0 to 46 months after vaccination starts
description: Number of deaths in hospitalized children stratified by gender in children aged 1-59 months.
measure: Number of malaria associated deaths in hospitalised children by gender
time frame: From 0 to 46 months after vaccination starts
description: Number of malaria specific deaths stratified by gender in hospitalized children aged 1-59 months.
measure: Number of children with a diagnosis of severe malaria
time frame: From 0 to 30 months after vaccination starts
description: Hospital admissions with malaria which meet WHO criteria for a diagnosis of severe malaria.
measure: Number of deaths excluding those attributed to trauma, poisoning and drowning
time frame: From 0 to 46 months after vaccination starts
description: Number of non traumatic deaths in children aged 1-59 months.
measure: Number of children with a diagnosis of aetiology confirmed meningitis
time frame: 30 months after vaccination starts
description: Number of hospital admissions which meet WHO criteria for a diagnosis of aetiologically confirmed meningitis admitted to sentinel hospitals
measure: Number of children with a diagnosis of suspected meningitis
time frame: From 0 to 30 months after vaccination starts
description: Number of hospital admissions which meet WHO criteria for a diagnosis of suspected meningitis admitted to sentinel hospitals
measure: Number of children with a diagnosis of probable meningitis
time frame: From 0 to 30 months after vaccination starts
description: Number of hospital admissions which meet WHO criteria for a diagnosis of probable meningitis admitted to sentinel hospitals
measure: Number of children with a diagnosis of malaria
time frame: From 0 to 30 months after vaccination starts
description: Number of hospital admissions which meet WHO criteria for a diagnosis of malaria admitted to sentinel hospitals
measure: Number of children with a non-malaria diagnosis
time frame: From 0 to 30 months after vaccination starts
description: Number of hospital admissions which do not meet WHO criteria for a diagnosis of malaria admitted to sentinel hospitals
measure: Number of children with a diagnosis of anaemia
time frame: From 0 to 30 months after vaccination starts
description: Number of hospital admissions which meet WHO criteria for a diagnosis of anaemia admitted to sentinel hospitals . Anaemia is haemoglobin less than 11g/dL.
measure: Number of children who have received all their routine EPI vaccines as recommended by their national immunization schedule
time frame: At 18 and 30 months after vaccination starts
description: Routine EPI vaccines include all doses of OPV, pentavalent, rotavirus, pneumococcal and measles vaccines
measure: Number of children who have received all the recommended malaria prevention and control measures
time frame: At 18 and 30 months after vaccination starts
description: Recommended malaria prevention and control measures include insecticide treated bed nets, IPTi and indoor residual spraying.
measure: Number of children who have received all of the other key childhood interventions
time frame: At 18 and 30 months after vaccination starts
description: Other key childhood interventions include anti-helminth administration (deworming) and Vitamin A supplementation
arm group label: Feasibility survey
description: These will be children living in the vaccinating and in non-vaccinating areas aged less than 5 years of age. For the midline household survey, this would be restricted to children aged 12-23 months of age.
arm group label: Sentinel hospital surveillance
description: These will be children living in the vaccinating and in non-vaccinating areas aged less than 5 years of age who are hospitalized in the 18 sentinel hospitals.
arm group label: Community mortality surveillance
description: These will be children whose deaths are reported in the vaccinating and in non-vaccinating areas aged less than 5 years of age .
intervention type: Other
intervention name: Feasibility survey
description: A survey questionnaire will be administered at each household. At the baseline household survey, each child aged less than 5 years will be tested for malaria using a rapid malaria test.
arm group label: Feasibility survey
intervention type: Other
intervention name: Sentinel hospital surveillance
description: Cerebrospinal samples will be collected from all children hospitalised and suspected of having meningitis.
arm group label: Sentinel hospital surveillance
intervention type: Other
intervention name: Community mortality surveillance
description: A verbal autopsy will be performed
arm group label: Community mortality surveillance
Cerebrospinal fluid
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 1 Month
maximum age: 59 Months
healthy volunteers: Accepts Healthy Volunteers
last name: Don Mathanga, PhD
role: Principal Investigator
affiliation: College of Medicine, Malawi
last name: Kwaku Poku Asante, PhD
role: Principal Investigator
affiliation: Kintampo Health Research Centre, Ghana
last name: Aaron Samuels, MD
role: Principal Investigator
affiliation: CDC-Kenya Malaria Program
facility: 
facility: 
facility: 
country: Ghana
country: Kenya
country: Malawi
url: https://www.who.int/docs/default-source/immunization/mvip/mvip-milestones-to-programme-development-final.pdf?Status=Temp&sfvrsn=14768db0_2
description: Key milestones in the development of the Malaria Vaccine Implementation Programme (MVIP): from pilot recommendation to vaccine introduction
citation: Malaria vaccine: WHO position paper-January 2016. Wkly Epidemiol Rec. 2016 Jan 4;91(4):33-51. No abstract available. English, French.
PMID: 26829826
citation: RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015 Jul 4;386(9988):31-45. doi: 10.1016/S0140-6736(15)60721-8. Epub 2015 Apr 23. Erratum In: Lancet. 2015 Jul 4;386(9988):30.
PMID: 25913272
responsible party type: Principal Investigator
investigator affiliation: World Health Organization
investigator full name: Patricia Njuguna
investigator title: Medical Officer
mesh term: Malaria
mesh term: Malaria, Falciparum
provided document: 
provided document: 