Examine Safety and Immune Responses of GSK 257049 Vaccine When Administered to Infants Living in a Malaria-endemic Region

Study Overview
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Brief Summary
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GSK Biologicals is developing in partnership with the Program for Appropriate Technology in Health (PATH) Malaria Vaccine Initiative a candidate malaria vaccine 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 Plasmodium falciparum. The vaccine would also provide protection against infection with hepatitis B virus (HBV). This trial is being carried out following the demonstration of efficacy of a previous version of the malaria candidate 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 order to integrate the malaria vaccine into the Expanded Program on Immunization (EPI) regimen, in malaria-endemic regions, for this trial, a 0.5 ml dose of GSK 257049 vaccine has been developed. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed Description
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All infants participating in this phase I/IIb study will receive TETRActHib (a licensed diphtheria-tetanus-pertussis Haemophilus influenzae vaccine manufactured by Aventis Pasteur) by IM injection in their right thigh at 8, 12, and 16 weeks; They will be randomized to receive either the candidate malaria vaccine, GSK 257049 vaccine (0.5 ml dose) or Engerix-B (a licensed hepatitis B vaccine manufactured by GSK Biologicals) by IM injection in their left thigh at 10, 14, 18 weeks. Infants will be followed-up daily for 7 days after each vaccine dose for evaluation of safety and reactogenicity. There will be a 14-day follow-up period after each dose of TETRActHib and after Dose 1 and Dose 2 of GSK 257049 vaccine or Engerix-B, and a one month follow-up period after Dose 3 of GSK 257049 vaccine or Engerix-B for reporting unsolicited symptoms. Serious adverse events will be recorded throughout the 14 month study period. A small amount of blood (2 ml = 1/2 teaspoon) will be obtained at four different time points to measure the immune response elicited by the vaccines administered during this study period. Preliminary indication of vaccine efficacy in this age group will be established by actively monitoring for infection with Plasmodium falciparum.

Official Title
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A Phase I/IIb Randomized, Double-blind, Controlled Study of the Safety, Immunogenicity and Proof-of-concept of RTS,S/AS02D, a Candidate Malaria Vaccine in Infants Living in a Malaria-endemic Region

Conditions
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Malaria

Intervention / Treatment
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* Biological: RTS,S/AS02D
* Biological: TETRActHib™
* Biological: Engerix-B®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A male or female infant of between 6 and 12 weeks of age at the time of first vaccination. Written informed consent obtained from the parent(s) or guardian(s) of the subject Free of obvious health problems as established by medical history and clinical examination before entering into the study. Born to a mother who is hepatitis B surface antigen (HBsAg) negative and human immunodeficiency virus (HIV) negative. Born after a normal gestation period (between 36 and 42 weeks). Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol should be enrolled in the study. Exclusion Criteria: Bacillus Calmette-Guérin tuberculosis vaccine (BCG) administration within one week of proposed administration of a study vaccine. Use of any investigational or non-registered drug or vaccine other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period. Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period. Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs since birth Any chronic drug therapy to be continued during the study period. Previous vaccination with diphtheria, tetanus, pertussis, Haemophilus influenzae type b or hepatitis B vaccines. Major congenital abnormality. Serious acute or chronic illness determined by clinical, physical examination and laboratory screening tests Any medically diagnosed or suspected immunodeficient condition based on medical history and physical examination A family history of congenital or hereditary immunodeficiency. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. History of any neurological disorders or seizures. Maternal death. Hemoglobin < 80 g/L Simultaneous participation in any other clinical trial. Same sex twin Any other findings that the investigator feels would increase the risk of having an adverse outcome from participation in the trialModerate malnutrition at screening

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 12 Weeks

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RTS,S/AS02D Group<br>Subjects aged between 6 and 12 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of RTS,S/AS02D at days 14, 44 and 74 and a 3-dose vaccination course of TETRActHib™ vaccine at days 0, 30 and 60. The RTS,S/AS02D vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh. | Biological: RTS,S/AS02D<br>* 3-dose intramuscular injection in the thigh<br>Biological: TETRActHib™<br>* 3-dose intramuscular injection in the thigh.<br>|
| Active Comparator: Engerix-B Group<br>Subjects aged between 6 and 12 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of Engerix-B® vaccine at days 14, 44 and 74 and a 3-dose of TETRActHib™ vaccine at days 0, 30 and 60. The Engerix-B® vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh. | Biological: TETRActHib™<br>* 3-dose intramuscular injection in the thigh.<br>Biological: Engerix-B®<br>* 3-dose intramuscular injection in the thigh.<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). | SAEs were defined as medical occurrences that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. | From Month 0 to Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Serious Adverse Events (SAEs). | SAEs were defined as medical occurrences that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. | Throughout the entire study period (from Month 0 to Month 14) | 
| Concentrations of Antibodies Against Hepatitis B (Anti-HB) | Concentrations were expressed as geometric mean concentrations (GMCs) in milli-international unit per milliliter (mIU/mL). The seroprotection cut-off of the assay was 10 mIU/mL. | Prior to vaccination at Month 0 (PRE) and 1 month post Dose 3 of Engerix-B® or RTS,S/AS02D vaccine (Day 104). | 
| Concentrations of Anti-circumsporozoite Protein (Anti-CS) Antibodies. | Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations are expressed as geometric mean concentrations (GMCs) in ELISA unit per milliliter (EL.U/mL). The seropositivity cut-off of the assay was 0.5 EL.U/mL. | Prior to vaccination at Month 0 (PRE), 1 month post Dose 3 of Engerix-B® or RTS,S/AS02D vaccine (Day 104) and 3½ months post Dose 3 of Engerix-B® or RTS,S/AS02D vaccine (Day 180). | 
| Concentrations of Antibodies Against Anti-diphtheria (Anti-D) | Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in international unit per milliliter (IU/mL). The seroprotection cut-off of the assay was 0.1 IU/mL. | At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine) | 
| Concentrations of Antibodies Against Tetanus (Anti-T) | Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in international unit per milliliter (IU/mL). The seroprotection cut-off of the assay was 0.1 IU/mL. | At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine) | 
| Concentrations of Anti-Bordetella Pertussis Toxin Antibodies (Anti-BPT). | Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in ELISA unit per milliliter (EL.U/mL). The seropositivity cut-off of the assay was 15 EL.U/mL. | At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine) | 
| Concentrations of Anti-polyribosyl Ribitol Phosphate Antibodies (Anti-PRP). | Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in microgram per milliliter (µg/mL). The seroprotection cut-off of the assay was 0.15 µg/mL. | At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine) | 
| Time to First Malaria Infection | Malaria infection by Plasmodium falciparum (P. falciparum) was detected by active detection of infection (ADI) and passive case detection (PCD), and was defined as the presence of P. falciparum asexual parasitemia above 0 per microliter (µL) on Giemsa stained thick blood films. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported (n) over the period elapsed until the event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group. | Over the period starting 14 days after Dose 3 of RTS,S/AS02D or Engerix-B® vaccine and extending for 12 weeks thereafter (from Month 2.5 to Month 6) | 
| Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum) | 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. | At Month 6 (3½ months post Dose 3 of RTS,S/AS02D or Engerix-B® vaccine) | 
| Plasmodium Falciparum (P. Falciparum) Parasite Density in Subjects Prevalent for Parasitemia | The parasite density in subjects prevalent for P. falciparum parasitemia (subjects with the presence of P. falciparum asexual parasitemia above 0 per microliter (µL) on Giemsa stained thick blood films), was detected at a cross sectional time point 3 ½ months after administration of Dose 3 of RTS,S/AS02D or Engerix-B® vaccine (Month 6). Parasite density is expressed as mean, minimum and maximum density in parasite per µL. | At Month 6 (3½ months post Dose 3 of RTS,S/AS02D or Engerix-B® vaccine) | 
| Number of Subjects With Solicited Local Symptoms. | Assessed solicited local symptoms were pain and swelling at injection site. | During the 7 day (Days 0-6) follow-up period after any vaccination with TETRActHib™ vaccine. | 
| Number of Subjects With Solicited Local Symptoms. | Assessed solicited local symptoms were pain and swelling at injection site. | During the 7 day (Days 0-6) follow-up period after any vaccination with Engerix-B® or RTS,S/AS02D vaccine. | 
| Number of Subjects With Solicited General Symptoms. | Assessed solicited general symptoms were drowsiness, fever, irritability and loss of appetite. Fever was defined as axillary temperature equal or above (≥) to 37.5 degrees Celsius (C). | During the 7 day (Days 0-6) follow-up period after any vaccination with TETRActHib™ vaccine | 
| Number of Subjects With Solicited General Symptoms. | Assessed solicited general symptoms were drowsiness, fever, irritability and loss of appetite. Fever was defined as axillary temperature equal or above (≥) to 37.5 degrees Celsius (C). | During the 7 day (Days 0-6) follow-up period after any vaccination with Engerix-B® or RTS,S/AS02D vaccine | 
| Number of Subjects With Unsolicited Adverse Events (AEs). | An unsolicited AE is any AE (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) 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. | During the 14 day (Days 0-13) follow-up period after any vaccination with of TETRActHib™ vaccine | 
| Number of Subjects With Unsolicited Adverse Events (AEs). | An unsolicited AE is any AE (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) 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. | During the 14 day (Days 0-13) follow-up period after vaccination with any among Doses 1 and 2 of Engerix-B® or RTS,S/AS02D vaccine. | 
| Number of Subjects With Unsolicited Adverse Events (AEs). | An unsolicited AE is any AE (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) 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. | During the 30 day (Days 0-29) follow-up period after vaccination with Dose 3 of Engerix-B® or RTS,S/AS02D vaccine. |