An Extension to Study MALARIA-055 PRI (NCT00866619) to Evaluate the Long-term Efficacy, Safety and Immunogenicity of GSK Biologicals' Candidate Malaria Vaccine in Infants and Children in Africa

Study Overview
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Brief Summary
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The purpose of this study is to conduct long-term surveillance for efficacy, safety and immunogenicity of the GSK Biologicals RTS,S/AS01E candidate Plasmodium falciparum malaria vaccine in infants and children in Africa following a primary vaccination series (NCT00866619). No new subjects will be enrolled in this extension study.

Official Title
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Extension to Study MALARIA-055 PRI (NCT00866619) for Evaluation of Long-term Efficacy, Safety and Immunogenicity of GSK Biologicals' Candidate Malaria Vaccine (SB257049) in Infants and Children in Africa

Conditions
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Malaria

Intervention / Treatment
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* Procedure: Blood sampling
* Biological: Malaria Vaccine 257049 (MALARIA-055 PRI)
* Biological: Meningococcal C Conjugate Vaccine (MALARIA-055 PRI)
* Biological: Cell-culture rabies vaccine (MALARIA-055 PRI)
* Biological: TritanrixHepB/Hib (MALARIA-055 PRI)
* Biological: Polio Sabin Oral Polio Vaccine (GSK) (MALARIA-055 PRI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects' parent(s)/ Legally Acceptable Representative (LARs) who, in the opinion of the investigator, can and will comply with the requirements of the protocol. Subjects who were enrolled and who received at least one vaccine dose in the primary study MALARIA-055 PRI NCT00866619 and who did not withdraw consent (except those who moved away from the area) during the primary study MALARIA-055 PRI NCT00866619. Written informed consent obtained from the parent(s)/LAR(s) of the subject. Exclusion Criteria: Child in care. Use of any investigational or non-registered product or planned use during the study period.

Ages Eligible for Study
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Minimum Age: 42 Months
Maximum Age: 9 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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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK257049 Group<br>Male or female infants (between and including 6 to 12 weeks of age)/children (between and including 5 to 17 months of age) received 3 doses of GSK257049 malaria vaccine (co-administered with Polio Sabin and Tritanrix HepB/Hib vaccines, for the infants subgroup) on a 0-1-2-month schedule, and a booster dose of GSK257049 malaria vaccine (co-administered with Polio Sabin, for the infants subgroup) at Month 20 during the primary study MALARIA-055 PRI (NCT00866619). Vaccines were administered intramuscularly: in the anterolateral left thigh (GSK257049 vaccine); left deltoid (GSK257049 booster dose); anterolateral right thigh (Tritanrix HepB/Hib vaccine); orally: Polio Sabin vaccine. No vaccination was administered during this study. | Procedure: Blood sampling<br>* Annual blood sampling (Year 1, Year 2 and Year 3) during the present study.<br>Biological: Malaria Vaccine 257049 (MALARIA-055 PRI)<br>* Administered intramuscularly into the left deltoid, during the MALARIA-055 study (NCT00866619).<br>Biological: TritanrixHepB/Hib (MALARIA-055 PRI)<br>* Administered intramuscularly into the left deltoid, during the MALARIA-055 study (NCT00866619).<br>Biological: Polio Sabin Oral Polio Vaccine (GSK) (MALARIA-055 PRI)<br>* Administered orally, during the MALARIA-055 study (NCT00866619).<br>|
| Active Comparator: GSK257049 Comparator Group<br>Male or female infants (between and including 6 to 12 weeks of age)/children (between and including 5 to 17 months of age) received 3 doses of GSK257049 malaria vaccine (co-administered with Polio Sabin and Tritanrix HepB/Hib vaccines, for the infants subgroup) on 0-1-2-month schedule, and a booster dose of Menjugate vaccine (co-administered with Polio Sabin, for the infants subgroup) at Month 20 during the primary study MALARIA-055 PRI (NCT00866619). Vaccines were administered intramuscularly: in the anterolateral left thigh (GSK257049 vaccine); anterolateral right thigh (Tritanrix HepB/Hib vaccine); orally: Polio Sabin vaccine. No vaccination was administered during this study. | Procedure: Blood sampling<br>* Annual blood sampling (Year 1, Year 2 and Year 3) during the present study.<br>Biological: Malaria Vaccine 257049 (MALARIA-055 PRI)<br>* Administered intramuscularly into the left deltoid, during the MALARIA-055 study (NCT00866619).<br>Biological: Meningococcal C Conjugate Vaccine (MALARIA-055 PRI)<br>* Administered intramuscularly into the left deltoid, during the MALARIA-055 study (NCT00866619).<br>* Other names: Menjugate;Biological: TritanrixHepB/Hib (MALARIA-055 PRI)<br>* Administered intramuscularly into the left deltoid, during the MALARIA-055 study (NCT00866619).<br>Biological: Polio Sabin Oral Polio Vaccine (GSK) (MALARIA-055 PRI)<br>* Administered orally, during the MALARIA-055 study (NCT00866619).<br>|
| Active Comparator: VeroRab/Menjugate Comparator Group<br>Male or female infants (between and including 6 to 12 weeks of age)/children (between and including 5 to 17 months of age) received 3 doses of VeroRab vaccine (children subgroup) or Menjugate vaccine (co-administered with Polio Sabin and Tritanrix HepB/Hib vaccines, for the infants subgroup) on 0-1-2-month schedule, and a booster dose of Menjugate vaccine (co-administered with Polio Sabin, for the infants subgroup) at Month 20 during the primary study MALARIA-055 PRI (NCT00866619). Vaccines were administered intramuscularly: left deltoid (VeroRab vaccine and Menjugate vaccine); anterolateral right thigh (Tritanrix HepB/Hib vaccine); orally: Polio Sabin vaccine. No vaccination was administered during this study. | Procedure: Blood sampling<br>* Annual blood sampling (Year 1, Year 2 and Year 3) during the present study.<br>Biological: Meningococcal C Conjugate Vaccine (MALARIA-055 PRI)<br>* Administered intramuscularly into the left deltoid, during the MALARIA-055 study (NCT00866619).<br>* Other names: Menjugate;Biological: Cell-culture rabies vaccine (MALARIA-055 PRI)<br>* Administered intramuscularly into the left deltoid, during the MALARIA-055 study (NCT00866619).<br>* Other names: VeroRab;Biological: TritanrixHepB/Hib (MALARIA-055 PRI)<br>* Administered intramuscularly into the left deltoid, during the MALARIA-055 study (NCT00866619).<br>Biological: Polio Sabin Oral Polio Vaccine (GSK) (MALARIA-055 PRI)<br>* Administered orally, during the MALARIA-055 study (NCT00866619).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Severe Malaria Meeting Case Definition 1 | Case definition 1 for severe malaria was defined as an episode of malaria with positive Plasmodium falciparum asexual parasitemia (within -1 to +3 days of admission) and with one or more marker of disease severity: Prostration, respiratory distress, Blantyre score equal to or less than (≤) 2, seizures 2 or more, hypoglycemia below (<) 2.2 millimoles per liter (mmol/L), acidosis BE ≤ -10.0 mmol/L, lactate ≥ 5.0 mmol/L or anemia < 5.0 grams per deciliter (g/dL). The incidence of severe malaria for case definition 1 is expressed as a person year rate for each group (n/T), representing the number of events (n) reported over the risk period, which was counted in days and expressed as person years at risk (T). | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 
| Incidence of Severe Malaria Meeting Case Definition 2. | Case definition 2 for severe malaria was defined as an episode of malaria with positive Plasmodium falciparum asexual parasitemia (within -1 to +3 days of admission) and with one or more marker of disease severity: Prostration, respiratory distress, Blantyre score equal to or less than (≤) 2, seizures 2 or more, hypoglycemia below (<) 2.2 millimoles per liter (mmol/L), acidosis BE ≤ -10.0 mmol/L, lactate ≥ 5.0 mmol/L or anemia < 5.0 grams per deciliter (g/dL) or SAE report including preferred terms (Malaria, Plasmodium falciparum infection or Cerebral malaria) within -1 to +3 days of admission. The incidence of severe malaria for case definition 2 is expressed as a person year rate for each group (n/T), representing the number of events (n) reported over the risk period, which was counted in days and expressed as person years at risk (T). | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Clinical Malaria Meeting Case Definition | Clinical malaria was defined as an episode of malaria with positive Plasmodium falciparum asexual parasitemia, accompanied by the presence of fever (axillary temperature ≥ 37.5°C ) at the time of presentation or history of fever within 24 hours of presentation and occurring in a child who was unwell and brought for treatment to a healthcare facility. The incidence of clinical malaria for case definition 1 is expressed as a person year rate for each group (n/T), representing the number of events (n) reported over the risk period, which was counted in days and expressed as person years a t risk (T). Due to late protocol approvals and retrospective data collection the sites did not collect the data according to protocol and as such the case definition cannot be applied. For the final analysis, specific case definitions based on available data were developed. | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 
| Number of Subjects With Malaria Hospitalization Meeting Case Definition 1. | Malaria hospitalization, case definition 1, was defined as a medical hospitalization with confirmed positive Plasmodium falciparum asexual parasitemia (excludes planned admissions for medical investigation/care or elective surgery and trauma). | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 
| Number of Subjects With Malaria Hospitalization Meeting Case Definition 2. | Malaria hospitalization, case definition 2, was defined as a hospitalization for which, in the judgment of the principal investigator, Plasmodium falciparum infection was the sole or a major contributing factor to the presentation. | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 
| Number of Subjects With Prevalent Parasitemia | Prevalent parasitemia (PP) was defined as a documented Plasmodium falciparum asexual parasite density greater than (>) 0 parasites/µL, identified at an annual visit. | At Years 1, 2 and 3 | 
| Number of Subjects With Prevalent Severe Anemia (Level of Hemoglobin <5g/dL) | Prevalent severe anemia (PSA) was defined as a documented hemoglobin lower than (<) 5.0 grams per deciliter (g/dL), identified at an annual visit. | At Years 1, 2 and 3 | 
| Number of Subjects With Prevalent Moderate Anemia (Level of Hemoglobin <8g/dL) | Prevalent moderate anemia (PMA) was defined as a documented hemoglobin < 8.0 g/dL, identified at an annual visit. | At Years 1, 2 and 3 | 
| Incidence of Severe Malaria Meeting Case Definition 1. | Case definition 1 for severe malaria was defined as an episode of malaria with positive Plasmodium falciparum asexual parasitemia (within -1 to +3 days of admission) and with one or more marker of disease severity: Prostration, respiratory distress, Blantyre score equal to or less than (≤) 2, seizures 2 or more, hypoglycemia below (<) 2.2 millimoles per liter (mmol/L), acidosis BE ≤ -10.0 mmol/L, lactate ≥ 5.0 mmol/L or anemia < 5.0 grams per deciliter (g/dL). The incidence of severe malaria for case definition 1 is expressed as a person year rate for each group (n/T), representing the number of events (n) reported over the risk period, which was counted in days and expressed as person years at risk (T). | From Month 0 (study start of Malaria-055) to Year 3 (study end of Malaria-076) | 
| Incidence of Severe Malaria Meeting Case Definition 2. | Case definition 2 for severe malaria was defined as an episode of malaria with positive Plasmodium falciparum asexual parasitemia (within -1 to +3 days of admission) and with one or more marker of disease severity: Prostration, respiratory distress, Blantyre score equal to or less than (≤) 2, seizures 2 or more, hypoglycemia below (<) 2.2 millimoles per liter (mmol/L), acidosis BE ≤ -10.0 mmol/L, lactate ≥ 5.0 mmol/L or anemia < 5.0 grams per deciliter (g/dL) or SAE report including preferred terms (Malaria, Plasmodium falciparum infection or Cerebral malaria) within -1 to +3 days of admission. The incidence of severe malaria for case definition 2 is expressed as a person year rate for each group (n/T), representing the number of events (n) reported over the risk period, which was counted in days and expressed as person years at risk (T). | From Month 0 (study start of Malaria-055) to Year 3 (study end of Malaria-076) | 
| Incidence of Clinical Malaria Meeting Case Definition | Clinical malaria was defined as an episode of malaria with positive Plasmodium falciparum asexual parasitemia, accompanied by the presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation or history of fever within 24 hours of presentation and occurring in a child who was unwell and brought for treatment to a healthcare facility. The incidence of clinical malaria for case definition 1 is expressed as a person year rate for each group (n/T), representing the number of events (n) reported over the risk period, which was counted in days and expressed as person years at risk (T). Due to late protocol approvals and retrospective data collection the sites did not collect the data according to protocol and as such the case definition cannot be applied. For the final analysis, specific case definitions based on available data were developed. | From Month 0 (study start of Malaria-055) to Year 3 (study end of Malaria-076) | 
| Number of Subjects With Malaria Hospitalization Meeting Case Definition 1. | Malaria hospitalization, case definition 1, was defined as a medical hospitalization with confirmed positive Plasmodium falciparum asexual parasitemia (excludes planned admissions for medical investigation/care or elective surgery and trauma). | From Month 0 (study start of Malaria-055) to Year 3 (study end of Malaria-076) | 
| Number of Subjects With Malaria Hospitalization Meeting Case Definition 2. | Malaria hospitalization, case definition 2, was defined as a hospitalization for which, in the judgment of the principal investigator, Plasmodium falciparum infection was the sole or a major contributing factor to the presentation. | From Month 0 (study start of Malaria-055) to Year 3 (study end of Malaria-076). | 
| Number of Subjects With Cerebral Malaria Meeting Both Case Definitions. | Cerebral malaria was defined as a positive P. falciparum asexual parasitemia (within -1 to +3 days of admission), accompanied either by the presence of a marker of disease severity (a Blantyre score ≤ 2) or a SAE report with 'cerebral malaria' as preferred term. | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 
| Number of Subjects With Fatal Malaria Meeting Case Definition 1. | Fatal malaria, case definition 1, was defined as a SAE report with preferred terms 'malaria', 'plasmodium falciparum infection', 'cerebral malaria' with confirmed positive Plasmodium falciparum asexual parasitemia associated with a fatal outcome (excludes planned admissions for medical investigation/care or elective surgery and trauma). | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 
| Number of Subjects With Fatal Malaria Meeting Case Definition 2. | Fatal malaria, case definition 2, was defined as a SAE report with preferred terms 'malaria', 'plasmodium falciparum infection', 'cerebral malaria' associated with a fatal outcome. | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 
| Number of Subjects With Cerebral Malaria | Cerebral malaria was defined as a positive P. falciparum asexual parasitemia (within -1 to +3 days of admission), accompanied either by the presence of a marker of disease severity (a Blantyre score ≤ 2) or a SAE report with 'cerebral malaria' as preferred term. | From Month 0 (study start of Malaria-055) to Year 3 (study end of Malaria-076). | 
| Number of Subjects With Fatal Malaria Meeting Case Definition 1. | Fatal malaria, case definition 1, was defined as a SAE report with preferred terms 'malaria', 'plasmodium falciparum infection', 'cerebral malaria' with confirmed positive Plasmodium falciparum asexual parasitemia associated with a fatal outcome (excludes planned admissions for medical investigation/care or elective surgery and trauma). | From Month 0 (study start of Malaria-055) to Year 3 (study end of Malaria-076). | 
| Number of Subjects With Fatal Malaria Meeting Case Definition 2. | Fatal malaria, case definition 2, was defined as a SAE report with preferred terms 'malaria', 'plasmodium falciparum infection', 'cerebral malaria' associated with a fatal outcome. | From Month 0 (study start of Malaria-055) to Year 3 (study end of Malaria-076). | 
| Number of Subjects Reporting Any, Related, Malaria and Fatal Serious Adverse Events (SAEs) | Malaria SAEs were defined as SAEs coded by MedDRA preferred term level as 'malaria', 'Plasmodium falciparum infection' or 'cerebral malaria. A serious adverse event was any untoward medical occurrence that: resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization or resulted in disability/incapacity. SAEs disclosed in this outcome are any SAEs , fatal SAEs, those that were related to vaccine administration in the primary study MALARIA-055 PRI (110021) and malaria hospitalization. | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 
| Number of Subjects Reporting Any Potential Immune-mediated Disorders (pIMDs) SAEs | Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology. Regardless of it being considered an AE or an SAE, it should have been reported per the SAE reporting rules. | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 
| Number of Subjects With Meningitis SAEs | For the further evaluation of the safety signal of meningitis all the cases occurring during the study were reported as SAE. Meningitis is defined as an SAE coded at lowest level terms code, coded by MedDRA preferred term level as: 'meningitis', 'meningitis haemophilus', 'meningitis meningococcal', 'meningitis salmonella', 'meningitis pneumococcal', 'meningitis staphylococcal', 'meningitis tuberculous', 'meningitis herpes', 'meningitis candida', 'meningitis enterococcal', 'meningitis enteroviral', 'meningitis neonatal', 'meningitis toxoplasmal', 'meningitis mumps', 'meningitis cryptococcal', 'meningitis histoplasma', 'meningitis trypanosomal', 'Neurosyphilis', 'meningitis leptospiral', 'meningitis listeria', 'meningitis in sarcoidosis' (code in preferred term 'cerebral sarcoidosis'), 'meningitis bacterial', 'meningitis viral', 'meningitis aseptic', 'meningitis fungal'. | From Year 0 to Year 3 (Starting January 2014 and ending December 2016) | 
| Antibody Concentrations Against Against Plasmodium Falciparum Circumsporozoite (Anti-CS) | Antibody concentrations were assessed by enzyme-linked immunosorbent assay (ELISA) and presented as geometric mean titers (GMTs). Seropositivity anti-CS antibody cut-off was 0.5 EU/mL for Malaria-055 time points and 1.9 EU/mL for Malaria-076 time points. | At screening, 1 month post Dose 3 (Month 3), 18 months post Dose 3 (Month 20), 1 month post Dose 4 (Month 21), 12 months post Dose 4 (Month 32) (of Malaria-055) and at Years 1, 2 and 3 (of Malaria-076) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infants, Efficacy, Children, Malaria, Plasmodium falciparum, Safety, Surveillance, Immunogenicity, RTS,S/AS01E, Africa