Efficacy of RTS,S/AS01 Vaccine Against Episodes of Malaria Due to P. Falciparum Infection in Children.

Study Overview
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Brief Summary
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This phase IIb trial is being done to find out if the RTS,S/AS01 vaccine helps to prevent children from falling ill with malaria and to evaluate vaccine safety. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Official Title
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A Study of the Efficacy Against Episodes of Clinical Malaria Due to P. Falciparum Infection of GSK Biologicals Candidate Vaccine RTS,S/AS01, Administered According to a 0,1,2-months Schedule in Children Aged 5 to 17 Months Living in Tanzania & Kenya

Conditions
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Malaria

Intervention / Treatment
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* Biological: GSK malaria vaccine 257049 Vaccine
* Biological: Sanofi-Pasteur's Human Diploid Cell Rabies Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A male or female child of between 5 months and 17 months of age at the time of first vaccination. Written or oral, signed or thumb-printed and witnessed informed consent obtained from the parent(s)/guardian(s) of the child.. Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol. Exclusion Criteria: Acute disease at the time of enrolment. Serious acute or chronic illness determined by clinical or physical examination and laboratory screening tests. Laboratory screening tests for haemoglobin, total white cell count, platelets, ALT and creatinine out of acceptable limits. Planned administration/administration of a vaccine not foreseen by the study within 30 days of the first dose of vaccine(s) with the exception of tetanus toxoid or scheduled diphtheria, pertussis or measles vaccine. Use of any investigational or non-registered drug or vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period. Administration of immunoglobulins, blood transfusions or other blood products within the three months preceding the first dose of study vaccine or planned administration during the study period. Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within 6 months prior to the first vaccine dose Previous participation in any other malaria vaccine trial. Simultaneous participation in any other clinical trial. Same sex twin. History of allergic reactions (significant IgE-mediated events) or anaphylaxis to previous immunizations. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. Any other findings that the investigator feels would increase the risk of having an adverse outcome from participation in the trial.

Ages Eligible for Study
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Minimum Age: 5 Months
Maximum Age: 17 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK257049 Group<br>Male or female subjects between 5 and 17 months of age at the time of first vaccination received 3 doses of GSK257049 vaccine administered intramuscularly in the left deltoid muscle at Days 0, 30 and 60. | Biological: GSK malaria vaccine 257049 Vaccine<br>* 3 dose intramuscular injection<br>* Other names: S/AS01E vaccine;|
| Active Comparator: Rabipur Group<br>Male or female subjects between 5 and 17 months of age at the time of first vaccination received 3 doses of Rabipur vaccine administered intramuscularly in the left deltoid muscle at Days 0, 30 and 60. | Biological: Sanofi-Pasteur's Human Diploid Cell Rabies Vaccine<br>* 3 dose intramuscular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of First Case of Malaria Meeting the Primary Case Definition | The first case of malaria meeting the primary case definition was defined as the first or only episodes with the presence of Plasmodium falciparum asexual parasitemia above (>) 2500 per microliter (μL) and the presence of fever greater than or equal to (≥) 37.5°C by active case detection (ACD) or passive case detection (PCD). Number of first case of malaria were assessed through estimate of vaccine efficacy (VE) adjusted or unadjusted for covariates, and are expressed in PYAR= number of episodes/Person Years at Risk. | Assessed over average of 7.8 months post Dose 3 (range 4.3 to 10.3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of First Case Malaria Meeting the Secondary Case Definition | The first case of malaria meeting the secondary case definition was defined as the first or only episodes with the presence of P.falciparum asexual parasitemia > 0 per μL and the presence of fever ≥ 37.5°C by active case detection (ACD) or passive case detection (PCD). Number of first case of malaria were assessed through estimate of vaccine efficacy (VE) adjusted or unadjusted for covariates, and are expressed in PYAR= number of episodes/Person Years at Risk. | Assessed over average of 7.8 months post Dose 3 (range 4.3 to 10.3 months) | 
| Multiple Events of Malaria Meeting the Primary Case Definition | Multiple episodes of malaria meeting the primary case definition was defined as episodes with the presence of P.falciparum asexual parasitemia > 25000 per μL and the presence of fever ≥ 37.5°C by active case detection (ACD) or passive case detection (PCD). Number of primary case of malaria were assessed through estimate of vaccine efficacy (VE) adjusted or unadjusted for covariates, and are expressed in PYAR= number of episodes/Person Years at Risk. | Assessed over average of 7.8 months post Dose 3 (range 4.3 to 10.3 months) | 
| Multiple Events of Malaria Meeting the Secondary Case Definition | Multiple episodes of malaria meeting the secondary case definition was defined as episodes with the presence of P.falciparum asexual parasitemia > 0 per μL and the presence of fever ≥ 37.5°C by active case detection (ACD) or passive case detection (PCD). Number of secondary case of malaria were assessed through estimate of vaccine efficacy (VE) adjusted or unadjusted for covariates, and are expressed in PYAR= number of episodes/Person Years at Risk. | Assessed over average of 7.8 months post Dose 3 (range 4.3 to 10.3 months) | 
| Number of Subjects Positive for P. Falciparum Parasitaemia |  | At the Cross-Sectional Visit that took place for each participant at on average 7.8 months post Dose 3 (range 4.3 to 10.3 months) | 
| Geometric Mean Density of Asexual P. Falciparum Parasite | Estimates of asexual P. falciparum parasite density were made at the investigator's sites according to laboratory standard operating procedures. Parasite density was presented as a geometric mean (GMean), expressed in parasite per microliters (μL). | At the Cross-Sectional Visit that took place for each participant at on average 7.8 months post Dose 3 (range 4.3 to 10.3 months) | 
| Haemoglobin Values at Cross-Sectional Visit | Haemoglobin values are expressed in grams per deciliter (g/dL). | At the Cross-Sectional Visit that took place for each participant at on average 7.8 months post Dose 3 (range 4.3 to 10.3 months) | 
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 swelling = swelling spreading beyond 20 millimeters (mm) of injection site. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were drowsiness, fever [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)], irritability and loss of appetite. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever higher than (>) 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination. | During the 7-day (Days 0-6) post-vaccination period following each dose and across doses | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. | Within the 30-day (Days 0-29) post-vaccination follow-up period | 
| 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 study period (Day 0 - Month 14) | 
| Number of Subjects With Hemoglobin Values Outside Normal Ranges With Toxicity Grades | Definitions for toxicity grading for hemoglobin were: Normal Hemoglobin = equal to or above (≥) 8.0 g/dL; Grade 1 Hemoglobin = under (<) 8.0 g/dL and above (>) 6.0 g/dL.; Grade 2 Hemoglobin = under (<) 6.0 g/dL. | At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29) | 
| Number of Subjects With White Blood Cell (WBC) Values Outside Normal Ranges With Toxicity Grades | Definitions for toxicity grading for WBC were: Normal WBC = ≥ 4.0 x 10^3 cells per microliters (cells/μL) or < 17 x 10^3 cells /μL; Grade 1 WBC = 2.5 to 4.0 x 10^3 cells/μL. | At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29) | 
| Number of Subjects With Platelet Values Outside Normal Ranges With Toxicity Grades | Definitions for toxicity grading for platelets were: Normal Platelets = ≥ 75 x 10^3 cells/μL; Grade 1 Platelets = 50 to 74 x 10^3 /μL; Grade 2 Platelets = 25 to 49 x 10^3 /μL; Grade 3 Platelets = < 25 x 10^3 /μL. | At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29) | 
| Number of Subjects With Alanine Aminotransferase (ALT) Values Outside Normal Ranges With Toxicity Grades | Definition for toxicity grading for ALT were: Normal ALT = ≤ 60 international units per liter (IU/L); Grade 1 ALT = 1.1 to 2.5 x Upper Limit of Normal (ULN); Grade 2 ALT = 2.6 to 5.0 x ULN. | At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29) | 
| Number of Subjects With Creatinine Values Outside Normal Ranges With Toxicity Grades | Definition for toxicity grading for creatinine were: Normal Creatinine = ≤ 60 micromols per liter (μmol/L); Grade 1 Creatinine = 1.1 to 1.5 x ULN; Grade 2 Creatinine = 1.6 to 3.0 x ULN. | At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29) | 
| Concentration of Antibodies Against the P. Falciparum Circumsporozoite (CS) Repeat Domain (Anti-CS) | Concentrations are presented as geometric mean concentrations (GMCs), expressed in enzyme-linked immunosorbent assay (ELISA) units per milliliter (EU/mL). | At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29) | 
| Concentration of Antibodies Against Hepatitis B Surface Antigen (Anti-HBs) | Concentrations are presented as geometric mean concentrations (GMCs), expressed in enzyme-linked immunosorbent assay (ELISA) units per milliliter (EU/mL). | At Day 0 and at Month 3 | 
| Frequency of Cluster of Differentiation 4 (CD4+) CS-specific T-cells | T-cells expressing at least one of the following cytokines are presented here: interleukin-2 [IL-2], tumor-necrosis factor-alpha [TNF-α] and interferon-gamma [IFN-γ]. Frequency is expressed in cells/million, as assessed by Intracellular Cytokine Assay (ICA). | Prior to vaccination (Day 0) | 
| Frequency of Cluster of Differentiation 8 (CD8+) CS-specific T-cells | T-cells expressing at least one of the following cytokines are presented here: interleukin-2 [IL-2], tumor-necrosis factor-alpha [TNF-α] and interferon-gamma [IFN-γ]. Frequency is expressed in cells/million, as assessed by Intracellular Cytokine Assay (ICA). | Prior to vaccination (Day 0) | 
| Frequency of Cluster of Differentiation 4 (CD4+) CS-specific T-cells | T-cells expressing at least one of the following cytokines are presented here: interleukin-2 [IL-2], tumor-necrosis factor-alpha [TNF-α] and interferon-gamma [IFN-γ]. Frequency is expressed in cells/million, as assessed by Intracellular Cytokine Assay (ICA). | At Month 3 | 
| Frequency of Cluster of Differentiation 8 (CD8+) CS-specific T-cells | T-cells expressing at least one of the following cytokines are presented here: interleukin-2 [IL-2], tumor-necrosis factor-alpha [TNF-α] and interferon-gamma [IFN-γ]. Frequency is expressed in cells/million, as assessed by Intracellular Cytokine Assay (ICA). | At Month 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RTS, Malaria, Plasmodium, S/AS01, Falciparum