Study of Safety, Immunogenicity and Efficacy of a Candidate Malaria Vaccine in Tanzanian Infants

Study Overview
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Brief Summary
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GSK Biologicals in partnership with the Malaria Vaccine Initiative at PATH is developing a candidate malaria vaccine GSK 257049 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). In order to integrate the malaria vaccine into the EPI regimen in malaria-endemic regions, a new variant RTS,S/AS02D (0.5 mL dose) 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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This is a phase 2b trial designed to evaluate the safety and immunogenicity of RTS,S/AS02D when co-administered with a multivalent DTPw/Hib (Aventis Pasteur's TETRActHib vaccine). Infants randomized to the control group will receive a licensed hepatitis B vaccine, Engerix-B in place of RTS,S/AS02D. Data pertaining to RTS,S/AS02D or Engerix-B will be collected in a double blinded manner; data relating to TETRActHib will be collected in an open fashion. Oral polio vaccine (OPV) will be administered at birth, 8, 12, 16 weeks in co-administration with other vaccines and will not be administered as part of this protocol. Antibody titers to OPV will not be assessed as part of this protocol.

Official Title
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A Phase IIb Randomized, Double-blind, Controlled Study of the Safety, Immunogenicity and Proof-of-concept of RTS,S/AS02D, a Candidate Malaria Vaccine, When Incorporated Into an Expanded Program on Immunization (EPI) Regimen That Includes DTPw/Hib in Infants Living in a Malaria-endemic Region.

Conditions
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Malaria, Malaria Vaccines

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


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: A male or female infant between 6 and 10 weeks 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 (e.g. return for follow-up visits). Born to a mother who is HBsAg negative & HIV negative. Born after a normal gestation period (between 36 and 42 weeks). Subjects who live within a 5 km radius of a dispensary. 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 out of range for haemoglobin, total white cell count, platelets, ALT and creatinine. Previous vaccination with diphtheria, tetanus, pertussis (whole-cell or acellular), Hemophilus influenzae type b or hepatitis B vaccines. BCG administration within one week of proposed administration of a study vaccine. Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days of the first dose of vaccine(s). 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 of immunosuppressants or other immune-modifying drugs within six 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. Maternal death. 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: 6 Weeks
Maximum Age: 10 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 10 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of the RTS,S/AS02D vaccine co-administered with the TETRActHib™ vaccine at Week 0, Week 4 (Month 1) and Week 8 (Month 2). 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>* Other names: S/AS02D;Biological: TETRActHib™<br>* 3-dose intramuscular injection in the thigh.<br>* Other names: DTPw/Hib;|
| Active Comparator: Engerix-B Group<br>Subjects aged between 6 and 10 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of Engerix-B® vaccine co-administered with the TETRActHib™ vaccine at Week 0, Week 4 (Month 1) and Week 8 (Month 2). The Engerix-B® vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh.. | Biological: Engerix-B®<br>* 3-dose intramuscular injection in the thigh.<br>Biological: TETRActHib™<br>* 3-dose intramuscular injection in the thigh.<br>* Other names: DTPw/Hib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 cut-off of the assay was the seroprotection cut-off of 10 mIU/mL. Month 3 results are the specific results for this primary outcome measure. | Prior to vaccination at Week 0 (PRE), at Month 2 and at Month 3. | 
| Number of Subjects With Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From Week 0 to Month 9. | 
| Concentrations of Antibodies Against 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 cut-off of the assay was the seroprotection cut-off of 0.1 IU/mL. Month 3 results are the specific results for this primary outcome measure. | Prior to vaccination at Week 0 (PRE), and at Month 3. | 
| 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 cut-off of the assay was the seroprotection cut-off of 0.1 IU/mL. Month 3 results are the specific results for this primary outcome measure. | Prior to vaccination at Week 0 (PRE), and at Month 3. | 
| Concentrations of Anti-polyribosyl Ribitol Phosphate Antibodies (Anti-PRP). | Concentrations were expressed as geometric mean concentrations (GMCs) in microgram per milliliter (µg/mL). The cut-off of the assay is the seroprotection cut-off value of 0.15 µg/mL. Month 3 results are the specific results for this primary outcome measure. | Prior to vaccination at Week 0 (PRE), and at Month 3. | 
| Number of Subjects With Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From Month 9 to Month 20. | 
| 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 cut-off of the assay was the seropositivity cut-off of 15 EL.U/mL. Month 3 results are the specific results for this primary outcome measure. | Prior to vaccination at Week 0 (PRE), and at Month 3. | 
| Number of Subjects With Hepatitis B Antibody (Anti-HB) Concentrations Equal to or Above (>=) the Seroprotection Cut-off Value | The seroprotection cut-off value was 10 milli-international units per milliliter (mIU/mL). Blood samples were collected prior to vaccination at Week 0 (PRE), at Month 2 and at Month 3. Month 3 results are the specific results for this primary outcome measure. | Prior to vaccination at Week 0 (PRE), at Month 2 and at Month 3. | 
| Number of Subjects With Anti-diphtheria Antibody (Anti-D) Concentrations Equal to or Above (>=) the Seroprotection Cut-off Value | Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). The seroprotection cut-off value was 0.1 international unit per milliliter (IU/mL). Blood samples were collected prior to vaccination at Week 0 (PRE), and at Month 3. Month 3 results are the specific results for this primary outcome measure. | Prior to vaccination at Week 0 (PRE), and at Month 3. | 
| Number of Subjects With Anti-tetanus Antibody (Anti-T) Concentrations Equal to or Above (>=) the Seroprotection Cut-off Value | Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). The seroprotection cut-off value was 0.1 international unit per milliliter (IU/mL). Blood samples were collected prior to vaccination at Week 0 (PRE), and at Month 3. Month 3 results are the specific results for this primary outcome measure. | Prior to vaccination at Week 0 (PRE), and at Month 3. | 
| Number of Subjects With Anti-polyribosyl Ribitol Phosphate Antibody (Anti-PRP) Concentrations Equal to or Above (>=) the Seroprotection Cut-off Value | Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). The seroprotection cut-off value was 0.15 microgram per milliliter (µg/mL). Blood samples were collected prior to vaccination at Week 0 (PRE), and at Month 3. Month 3 results are the specific results for this primary outcome measure. | Prior to vaccination at Week 0 (PRE), and at Month 3. | 
| Number of Subjects With Anti-Bordetella Pertussis Toxin Antibody (Anti-BPT) Concentrations Equal to or Above (>=) the Seropositivity Cut-off Value | Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). The seropositivity cut-off value was 15 ELISA units per milliliter (EL.U/mL). Blood samples were collected prior to vaccination at Week 0 (PRE), and at Month 3. Month 3 results are the specific results for this primary outcome measure. | Prior to vaccination at Week 0 (PRE), and at Month 3. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 cut-off of the assay was the seropositivity cut-off value of 0.5 EL.U/mL. | Prior to vaccination at Week 0 (PRE), at Month 2, at Month 3 and at Month 9. | 
| Number of Subjects With Solicited Local Symptoms. | Assessed solicited local symptoms were pain and swelling following vaccination with the RTS,S/AS02D or Engerix-B vaccine. | Within 7 days (Days 0-6) after vaccination with the RTS,S/AS02D or Engerix-B vaccine. | 
| Number of Subjects With Solicited Local Symptoms. | Assessed solicited local symptoms were pain and swelling following vaccination with the TETRActHib vaccine.. | Within 7 days (Days 0-6) after vaccination with the 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 above or equal to (>=) 37.5 degrees Celsius (°C). | Within 7 days (Days 0-6) after vaccination | 
| Number of Subjects With Unsolicited Adverse Events (AEs). | An unsolicited adverse event is any adverse event (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. | Within 30 days (Days 0-29) after vaccination | 
| Number of Subjects With Serious Adverse Events (SAEs) | 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, from Week 0 to Month 20. | 
| 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 or HBV vaccine and extending for 6 months thereafter (from Month 2.5 up to Month 9). | 
| Number of Subjects Prevalent for 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. | At Month 9 | 
| 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 7 months after administration of Dose 3 of RTS,S or HBV vaccine (Month 9). Parasite density is expressed as mean, minimum and maximum density in parasite per µL. This outcome for solely assessed in the Engerix-B Group, as no subject in the RTS,S/AS02D was assessed as prevalent for parasitemia. | At Month 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coccidiosis, Parasitic Diseases, Malaria, Falciparum, Malaria