Long-Term Follow-up of Children for a 2-Year Period to Confirm the Safety and Immunogenicity of GSK 257049 Vaccine

Study Overview
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Brief Summary
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The RTS,S/AS02A vaccine (or GSK 257049 vaccine), GSK Biologicals' candidate Plasmodium falciparum (P. falciparum) malaria vaccine is being developed for the routine immunization of infants and children living in malaria endemic areas. The vaccine would offer protection against malaria disease due to the parasite P. falciparum. The vaccine would also provide protection against infection with hepatitis B virus (HBV). This phase IIb trial is being carried out following the demonstration of efficacy of the candidate malaria vaccine in children in Mozambique: there, the vaccine demonstrated approximately 30% efficacy against clinical episodes of malaria and approximately 58% efficacy against severe malaria disease. In this study, the children from Mozambique (NCT= NCT00197041) are followed-up to assess the safety, immunogenicity and efficacy of the candidate malaria vaccine for a two year period commencing 21 months after Dose 1. This protocol posting deals with objectives & outcome measures of the extension phase at year 2. During this extension study, no new subjects will be recruited and no vaccine will be administered. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Official Title
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An Open Study for a 2-year Period to Confirm the Safety and Immunogenicity of the Candidate Malaria Vaccine RTS,S/AS02A in Mozambican Children Aged 1 to 4 Years at the Time of First Vaccine Dose.

Conditions
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Malaria

Intervention / Treatment
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* Biological: GSK Biologicals' candidate Plasmodium falciparum malaria vaccine 257049
* Biological: Engerix™-B
* Biological: Hiberix®
* Biological: Prevnar™
* Drug: sulfadoxine-pyrimethamine
* Drug: amodiaquine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Completion of Visit 7, Month 21 of 104297 (NCT= NCT00197041). Written informed consent obtained from the parent(s) or guardian(s) of the subject Exclusion criteria: Planned use of any investigational or non-registered drug or vaccine during the study period. Simultaneous participation in any other clinical trial

Ages Eligible for Study
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Minimum Age: 33 Months
Maximum Age: 69 Months

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: Cohort 1-RTS,S/AS02A <24M Group<br>Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection. | Biological: GSK Biologicals' candidate Plasmodium falciparum malaria vaccine 257049<br>* IM injection in the deltoid muscle<br>* Other names: S/AS02A vaccine;|
| Experimental: Cohort 1-RTS,S/AS02A ≥24M Group<br>Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection. | Biological: GSK Biologicals' candidate Plasmodium falciparum malaria vaccine 257049<br>* IM injection in the deltoid muscle<br>* Other names: S/AS02A vaccine;|
| Experimental: Cohort 2-RTS,S/AS02A <24M Group<br>Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. | Biological: GSK Biologicals' candidate Plasmodium falciparum malaria vaccine 257049<br>* IM injection in the deltoid muscle<br>* Other names: S/AS02A vaccine;Drug: sulfadoxine-pyrimethamine<br>* 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance<br>Drug: amodiaquine<br>* 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance<br>|
| Experimental: Cohort 2-RTS,S/AS02A ≥24M Group<br>Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 of the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. | Biological: GSK Biologicals' candidate Plasmodium falciparum malaria vaccine 257049<br>* IM injection in the deltoid muscle<br>* Other names: S/AS02A vaccine;Drug: sulfadoxine-pyrimethamine<br>* 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance<br>Drug: amodiaquine<br>* 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance<br>|
| Active Comparator: Cohort 1-Prevnar-Hiberix <24M Group<br>Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection. | Biological: Hiberix®<br>* IM injection in the deltoid muscle<br>Biological: Prevnar™<br>* IM injection in the deltoid muscle<br>|
| Active Comparator: Cohort 1-Engerix-B ≥24M Group<br>Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection. | Biological: Engerix™-B<br>* IM injection in the deltoid muscle<br>|
| Active Comparator: Cohort 2-Prevnar- Hiberix <24M Group<br>Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. | Biological: Hiberix®<br>* IM injection in the deltoid muscle<br>Biological: Prevnar™<br>* IM injection in the deltoid muscle<br>Drug: sulfadoxine-pyrimethamine<br>* 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance<br>Drug: amodiaquine<br>* 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance<br>|
| Active Comparator: Cohort 2-Engerix-B ≥24M Group<br>Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. | Biological: Engerix™-B<br>* IM injection in the deltoid muscle<br>Drug: sulfadoxine-pyrimethamine<br>* 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance<br>Drug: amodiaquine<br>* 1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Serious Adverse Events (SAEs) | Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | Throughout the entire study period: from Month 21 to Month 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-circumsporozoite Protein (CS) Antibody Concentrations. | Concentrations for anti-CS antibodies are presented as Geometric Mean Concentrations (GMCs), expressed in Enzyme-Linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off of 0.5 EL.U/mL. Subjects were pooled across age ranges for this outcome measure. | At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study). | 
| Anti-hepatitis B (HBs) Antibody Concentrations. | Concentrations are presented as geometric mean concentrations (GMCs), expressed in milli-international units per milliliter (mIU/mL). Anti-HBs antibody concentration levels were measured in blood samples from Cohort 2 only. | At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study). | 
| Time to First or Only Clinical Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Primary Case Definition | Malaria infection by Plasmodium falciparum was detected by passive case detection. A symptomatic PFMI episode of Primary Case Definition (PCD) was defined as the presence of P. falciparum asexual parasitaemia above 2500 per µL on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius at the time of presentation) occurring in an unwell child brought for treatment to a healthcare facility. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was solely performed on Cohort 1 subjects, with groups pooled across age ranges. | From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041 | 
| Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 1 | PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 1 was defined as the presence of P. falciparum asexual parasitaemia (any level if parasitemia) on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius) in an unwell child brought for treatment. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was solely performed on Cohort 1 subjects, with groups pooled across age ranges. | From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041 | 
| Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 2 | PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 2 was defined as the presence of P. falciparum asexual parasitaemia (any level if parasitemia) on Giemsa stained thick blood films in an unwell child brought for treatment with a history of fever (axillary temperature equal or above 37.5 degrees Celsius) within 24 hours or documented fever. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was performed on Cohort 1 subjects, with groups pooled across age ranges. | From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041 | 
| Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 3 | PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 3 was defined as the presence of P. falciparum asexual parasitaemia above 15000 per microliter (µL) on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius) in an unwell child brought for treatment to a healthcare facility. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges. | From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041 | 
| Number of Primary Case Definition Clinical Episodes of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) | PFMI was detected by passive case detection. A symptomatic PFMI episode of Primary Case Definition (PCD) was defined as the presence of P. falciparum asexual parasitaemia above 2500 per µL on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius at the time of presentation) occurring in an unwell child brought for treatment to a healthcare facility. The number of PFMI episodes (EPFMI) per person-year (pyr) was tabulated, using as unit EPFMI episode per pyr. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges. | From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041 | 
| Number of Subjects With Anemia. | Anemia was indicated by a hematocrit level (HL) below (<) 25%. The numbers of subjects with HL below (<) and above or equal (≥) 25 %, and with missing HL results were tabulated. In the tabulation below, the number of subjects falling into the HL ≥25% category corresponds to the number of subjects with anemia as asked per outcome. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges. | At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study). | 
| Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum) Parasitemia | Subjects prevalent for P. falciparum parasitemia were defined as subjects with the presence of P. falciparum asexual parasitemia above 0 per microliter (µL) on Giemsa stained thick blood films.Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges. | At Months 33 (M33) and 45 (M45) (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study). |