Safety and Immunogenicity of GSK Biologicals' Investigational Malaria Vaccine in HIV Infected Infants and Children

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and immunogenicity of the candidate malaria vaccine in HIV-infected infants and children

Detailed Description
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This protocol posting has been updated due to protocol Amendment 2.

Official Title
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Safety and Immunogenicity Study of GSK Biologicals' Plasmodium Falciparum Malaria Vaccine 257049 Administered to HIV Infected Infants and Children

Conditions
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Malaria

Intervention / Treatment
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* Biological: GSK Biological's Investigational Malaria Vaccine 257049
* Biological: Human Diploid Cell Vaccine (HDCV) or Purified Vero Cell Rabies Vaccine (PVRV, Verorab) (Aventis Pasteur);
* Biological: Purified Chick Embryo Cell Culture (PCEC) Rabies Vaccine (Rabipur or equivalent) (Novartis).


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects must satisfy ALL the following criteria at study entry: A male or female infant or child between and including 6 weeks to 17 months of age, at the time of first vaccination. Signed or thumb-printed informed consent obtained from the parent(s)/LAR(s) of the infant or child. Where parents/LARs are illiterate, the consent form will be countersigned by a witness. Subjects who the investigator believes that their parents/LARs can and will comply with the requirements of the protocol should be enrolled in the study. Subjects who are known to be HIV-infected (documented positive DNA PCR), whether taking HIV antiretroviral treatment (ART) or not. Subjects who are born following a normal gestation period. Exclusion Criteria: The following criteria should be checked at the time of study entry. If ANY exclusion criterion applies, the subject must not be included in the study: Acute disease at the time of enrolment. However, the presence of an illness listed as Grade I or Grade II (WHO pediatric AIDS clinical staging) will not of itself constitute an exclusion criterion. Enrolment should be deferred if axillary temperature is >=37.5°C. Grade III or Grade IV abnormality on screening laboratory blood sample. Grade III or IV AIDS at the time of enrolment (WHO pediatric AIDS clinical staging). Major congenital defects. Planned administration/administration of a vaccine not foreseen by the study protocol prior to or within 7 days of study vaccine. Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine 30 days preceding Dose°1 of study vaccine, or planned use during the study period. Previous participation in any other malaria vaccine trial. Simultaneous participation in another clinical trial including administration of experimental treatment. Same sex twins. 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 study vaccine. Child in care.

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 17 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Infants enrolled to this group will receive 3 doses of the experimental vaccine. | Biological: GSK Biological's Investigational Malaria Vaccine 257049<br>* All infants enrolled to group A will receive 3 doses of the experimental vaccine. The vaccine will be administered intramuscularly.<br>|
| Active Comparator: Group B<br>Infants enrolled to this group will receive 3 doses of the rabies comparator vaccine. | Biological: Human Diploid Cell Vaccine (HDCV) or Purified Vero Cell Rabies Vaccine (PVRV, Verorab) (Aventis Pasteur);<br>* To ensure consistent vaccine availability, three cell culture rabies vaccines from two manufacturers may be sourced for this trial (Aventis-Pasteur and Novartis). It will be ensured that an individual child will receive all 3 doses of cell culture rabies vaccine from the same product. The vaccine will be administered intramuscularly<br>Biological: Purified Chick Embryo Cell Culture (PCEC) Rabies Vaccine (Rabipur or equivalent) (Novartis).<br>* To ensure consistent vaccine availability, three cell culture rabies vaccines from two manufacturers may be sourced for this trial (Aventis-Pasteur and Novartis). It will be ensured that an individual child will receive all 3 doses of cell culture rabies vaccine from the same product. The vaccine will be administered intramuscularly.<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 assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | During the entire study period (from 30 days before Dose 1 up to Month 14) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Any and Grade 3 Solicited Local Symptoms | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond (>) 20 millimeters (mm) of injection site. | During the 7-day post-vaccination period following each dose and across doses: Day 1 through Day 7, Month 1 through Month 1 + 7 days (Day 37), Month 2 through Month 2 + 7 days (Day 67) | 
| Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms | Assessed solicited general symptoms were drowsiness, irritability, loss of appetite and fever [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)]. Any = occurrence of the symptom regardless of intensity grade. Grade 3 drowsiness = drowsiness that prevented normal activity. Grade 3 irritability/fussiness = crying that could not be comforted/prevented normal activity. Grade 3 loss of appetite = not eating at all. Grade 3 fever = fever > 39.0 °C. Related = symptom assessed by the investigator as causally related to the study vaccination. | During the 7-day post-vaccination period following each dose and across doses: Day 1 through Day 7, Month 1 through Month 1 + 7 days (Day 37), Month 2 through Month 2 + 7 days (Day 67) | 
| 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. | During the 30-day post-vaccination period (up to Day 90) | 
| Number of Subjects With Non-malaria Related SAEs | SAEs (excluding malaria, cerebral malaria and P. falciparum parasitemia) assessed include medical occurrences that result in death, are life-threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | During the entire study period (from 30 days before vaccine Dose 1 up to Month 14) | 
| Anti-circumsporozoite Protein of P. Falciparum (Anti-CS) Antibody Concentrations | Anti-CS antibody concentrations are presented as geometric mean concentrations (GMCs), expressed in ELISA units per milliliter (EL.U/mL). The reference seropositivity cut-off value was equal to or above (≥) 0.5 EL.U/mL. | Prior to vaccination (PRE) and one month post Dose 3 (Month 3) | 
| Anti-hepatitis B Surface Antigen (Anti-HBs) Antibody Titers | Anti-HBs antibody titers are presented as geometric mean titers (GMTs), expressed in milliinternational units per milliliter (mIU/mL). | Prior to vaccination (PRE) and one month post Dose 3 (Month 3) | 
| Anti-CS Antibody Concentrations | Anti-CS antibody concentrations are presented as geometric mean concentrations (GMCs), expressed in ELISA units per milliliter (EL.U/mL). The reference seropositivity cut-off value was equal to or above (≥) 0.5 EL.U/mL. | 12 months post Dose 3 (Month 14) | 
| Anti-HBs Antibody Titers | Anti-HBs antibody titers are presented as geometric mean titers (GMTs), expressed in mIU/mL. | 12 months post Dose 3 (Month 14) | 
| Number of Episodes With Clinical Malaria Disease According to Primary Case Definition | Primary case definition for clinical malaria: P. falciparum asexual parasitemia > 2500 parasites/μL and presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation and occurring in a child who was unwell and brought for treatment to a healthcare facility. | From Day 0 to Month 14 | 
| Number of Episodes With Severe Malaria According to Primary Case Definition | The number of episodes of severe malaria of primary case definition within and outside risk period. Primary case definition for severe malaria: P. falciparum > 2500 parasites per μL and with one or more marker of disease severity and without a diagnosis of co-morbidity. | From Day 0 to Month 14 | 
| Number of Subjects Affected by Prevalent Parasitemia and Prevalent Moderate Anemia | The number of subjects affected by prevalent asexual P. falciparum parasitemia and prevalent moderate anemia. Moderate anemia = hemoglobin < 8 g/dL. | 12 months post Dose 3 (Month 14) | 
| Asexual P. Falciparum Parasitemia Density | The number of subjects with a positive blood slide for asexual P. falciparum. | 12 months post Dose 3 (Month 14) | 
| Prevalent Hemoglobin Level | The prevalent hemoglobin level in subjects with a positive blood slide is reported as grams per deciliter (g/dl). | 12 months post Dose 3 (Month 14) | 
| HIV Viral Load | The HIV viral load is reported. Detectable HIV viral load: 400 or more copies/mL. | At baseline (PRE) and at one month (Month 3), 6 months (Month 8) and 12 months (Month 14) post Dose 3 | 
| Percentage of CD4+ Cells | The percentage of CD4+ cells is reported. | At baseline (PRE) and at one month (Month 3), 6 months (Month 8) and 12 months (Month 14) post Dose 3 | 
| CD4+ Absolute Cell Counts | The CD4+ absolute cell counts are reported. | At baseline (PRE) and at 1 month (Month 3), 6 months (Month 8) and 12 months (Month 14) post Dose 3 | 
| World Health Organization (WHO) HIV Clinical Classification Progression | Clinical staging was done at each time point according to the WHO HIV/AIDS clinical staging system. Clinical stages included: Stage 1 (asymptomatic or have persistent generalized lymphadenopathy), Stage 2 (mildly symptomatic stage - presenting with unexplained weight loss of less than 10 percent of total body weight, recurrent respiratory infections or dermatological conditions), Stage 3 (moderately symptomatic stage - presenting with weight loss of greater than 10 percent of total body weight, prolonged unexplained diarrhea or pulmonary tuberculosis, severe systemic bacterial infections or mucocutaneous conditions), Stage 4 (severely symptomatic stage which includes all of the AIDS-defining illnesses) Additional categories included deceased and missing. | At baseline (PRE), at study months 1 (Month 1) and 2 (Month 2) and at 1 month (Month 3), 6 months (Month 8) and 12 months (Month 14) post Dose 3 | 
| Growth Parameters: Weight, Age/Length and Middle Upper Arm Circumference for Age Z-score | The following growth parameters: weight, age/length and middle upper arm circumference for age z-score are reported. | At baseline (PRE), at Month 3 and at study end (Month 14) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plasmodium falciparum, schedule, HIV, malaria vaccine, EPI, Africa