Efficacy, Safety and Immunogenicity Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Schedules With or Without Fractional Doses, Early Dose 4 and Yearly Doses, in Children 5-17 Months of Age

Study Overview
=================
Brief Summary
-----------------
The study intends to establish proof of concept for a fractional dose schedule under conditions of natural exposure in children 5-17 months old at first vaccination. The study also aims to establish the role of third dose spacing in a fractional dose schedule, describe the effect of an earlier full fourth dose at Month 14 and describe the effect of multiple fractional or full yearly doses.

Detailed Description
-----------------
The current study intends to establish proof of concept (POC) for a fractional dose schedule under conditions of natural exposure. The study will be conducted in children 5-17 months old at first vaccination living in areas of mid to high malaria transmission, in line with the age group recommended by the World Health Organization (WHO) for the implementation of the RTS,S/AS01E vaccine. Results from this study will be critical in informing future possibilities for the development of vaccine-based strategies which, in combination with other interventions, may contribute to the malaria elimination agenda.

Official Title
-----------------
Efficacy, Safety and Immunogenicity Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Schedules With or With-out Fractional Doses, Early Dose 4 and Yearly Doses, in Children 5-17 Months of Age

Conditions
-----------------
Malaria

Intervention / Treatment
-----------------
* Biological: RTS,S/AS01E (Full dose)
* Biological: RTS,S/AS01E (1/5th dose)
* Biological: Rabies vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects' parent(s)/LAR(s) who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. return for follow-up visits). Signed or thumb-printed and witnessed informed consent obtained from the parent(s)/LAR(s) of the subject prior to performance of any study specific procedure. Where parent(s)/LAR(s) are illiterate, the consent form will be countersigned by an independent witness. A male or female between, and including, five and 17 months of age at the time of the first vaccination. Healthy subjects as established by medical history and clinical examination before entering into the study. Previously received three documented doses of diphtheria, tetanus, pertussis, hepatitis B vaccine (DTPHepB), and at least three doses of oral polio vaccine. Exclusion Criteria: Child in care. Use of a drug or vaccine that is not approved for that indication (by one of the following regulatory authorities: Food and Drug Administration [FDA; USA] or European Union member state or WHO [with respect to prequalification]) other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day -29 to Day 0), or planned use during the study period. Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe. Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone (0.5 mg/kg/day (for pediatric subjects) or equivalent. Inhaled and topical steroids are allowed. Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting seven days before each dose and ending seven days after each dose of vaccine administration. Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product (pharmaceutical product or device). Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). Family history of congenital or hereditary immunodeficiency. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines. History of anaphylaxis post-vaccination. History of any, or documented, serious adverse reaction to rabies vaccination. Contraindication to rabies vaccination (Rabipur is contraindicated in subjects with an history of a severe hypersensitivity to any of the ingredients in the vaccine. Note that the vaccine contains polygeline and residues of chicken proteins, and may contain traces of neomycin, chlortetracycline and amphotericin B). Major congenital defects. Serious chronic illness. Children with a past history of a neurological disorder or atypical febrile seizure (a febrile seizure is atypical if it meets one of the following criteria: not associated with fever; lasts > 5 minutes; focal (not generalized); followed by transient or persistent neurological abnormality; occurs in a child < 6 months of age). Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 37.5°C/99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C/100.4°F for rectal route. Subjects with a minor illness (such as mild diarrhea, mild upper respiratory infection) without fever may, be enrolled at the discretion of the investigator. Administration of immunoglobulins and/or any blood products during the period starting three months before the first dose of study vaccine or planned administration during the study period. Moderate or severe malnutrition at screening defined as weight for age or weight for height Z-score < -2. Hemoglobin concentration < 8 g/dl at screening. Same sex twins (to avoid misidentification). Maternal death. Prior receipt of an investigational malaria vaccine.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R012-20 Group<br>Subjects will receive full doses of RTS,S/AS01E at Month 0, Month 1, Month 2 and a full dose at Month 20. | Biological: RTS,S/AS01E (Full dose)<br>* Subjects will receive intramuscular injection of RTS,S/AS01E (full dose: 0.5 ml).<br>|
| Experimental: R012-14-mD Group<br>Subjects will receive a full dose of RTS,S/AS01E at Month 0, Month 1, Month 2 and yearly full doses at Month 14, Month 26, Month 38. | Biological: RTS,S/AS01E (Full dose)<br>* Subjects will receive intramuscular injection of RTS,S/AS01E (full dose: 0.5 ml).<br>|
| Experimental: Fx012-14-mFxD Group<br>Subjects will receive a full dose of RTS,S/AS01E at Month 0, Month 1 and RTS,S/AS01E 1/5th dose at Month 2, Month 14, Month 26, Month 38. | Biological: RTS,S/AS01E (Full dose)<br>* Subjects will receive intramuscular injection of RTS,S/AS01E (full dose: 0.5 ml).<br>Biological: RTS,S/AS01E (1/5th dose)<br>* Subjects will receive intramuscular injection of RTS,S/AS01E (1/5th dose: 0.1 ml).<br>|
| Experimental: Fx017-mFxD Group<br>Subjects will receive a full dose of RTS,S/AS01E at Month 0, Month 1 and RTS,S/AS01E 1/5th dose at Month 7, Month 20, Month 32. | Biological: RTS,S/AS01E (Full dose)<br>* Subjects will receive intramuscular injection of RTS,S/AS01E (full dose: 0.5 ml).<br>Biological: RTS,S/AS01E (1/5th dose)<br>* Subjects will receive intramuscular injection of RTS,S/AS01E (1/5th dose: 0.1 ml).<br>|
| Experimental: Control Group<br>Subjects will receive rabies vaccine at Month 0, Month 1, Month 2. | Biological: Rabies vaccine<br>* Subjects will receive intramuscular injection of rabies vaccine (0.1 ml).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence of clinical malaria meeting the primary case definition | The primary case definition will be P. falciparum asexual parasitemia greater than (>) 5000 parasites/microliters (μl) and presence of fever (axillary temperature greater than or equal to [≥] 37.5 degrees Celsius [°C]) at the time of presentation and occurring in a child who is unwell and brought for treatment to a healthcare facility. | From Month 2.5 up to Month 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence of clinical malaria meeting the primary and secondary case definitions | The primary case definition will be P. falciparum asexual parasitemia > 5000 parasites/μl and presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation and occurring in a child who is unwell and brought for treatment to a healthcare facility. The secondary case definition will be P. falciparum asexual parasitemia > 0 and presence of fever (axillary temperature ≥ 37.5°C) at the time of presentation or history of fever within 24 hours of presentation and occurring in a child who is unwell and brought for treatment to a healthcare facility. | From Day 0 up to Month 50 | 
| The occurrence of incident P. falciparum infections | Vaccine efficacy against incident P. falciparum infections defined by positive blood slide. | From Day 0 to Month 50 | 
| The prevalence of P. falciparum infections defined by positive blood slide at each cross-sectional survey | Prevalence of P. falciparum infections of each RTS,S/AS01E schedule at cross-sectional visits. | Monthly from Month 0-20 and every three months thereafter till study end (Month 50) | 
| Number of seropositive subjects for anti-circumsporozoite (anti-CS) antibodies (in a sub-cohort of first 25 subjects enrolled in each group per site) | A seropositive subject is defined as a subject with antibody concentrations ≥ 0.5 ELISA units per milliliter (EU/mL). | Before Dose 1, one month post-Dose 2 (group Fx017-mFxD only), before and one month post-Dose 3, before and one month after Dose 4, before and one month after each yearly dose and at study end (Month 50) | 
| Number of seropositive subjects for anti-hepatitis B (anti-HB) antibodies (in a sub-cohort of first 25 subjects enrolled in each group per site) | A seropositive subject is defined as a subject with antibody concentrations ≥ 10 milli-international units per milliliter (mIU/mL). | Before Dose 1, one month post-Dose 2 (group Fx017-mFxD only), before and one month post-Dose 3, before and one month after Dose 4, before and one month after each yearly dose and at study end (Month 50) | 
| Antibody concentrations for anti-CS (in a sub-cohort of first 25 subjects enrolled in each group per site) | Concentrations are expressed as geometric mean concentrations (GMC). | Before Dose 1, one month post-Dose 2 (group Fx017-mFxD only), before and one month post-Dose 3, before and one month after Dose 4, before and one month after each yearly dose and at study end (Month 50) | 
| Antibody concentrations for anti-HB (in a sub-cohort of first 25 subjects enrolled in each group per site) | Concentrations are expressed as geometric mean concentrations (GMC). | Before Dose 1, one month post-Dose 2 (group Fx017-mFxD only), before and one month post-Dose 3, before and one month after Dose 4, before and one month after each yearly dose and at study end (Month 50). | 
| Number of subjects with any, fatal and related serious adverse events (SAEs) | SAEs include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From Day 0 to Month 50 | 
| Number of subjects with any adverse events (AEs) and serious adverse events (SAEs) leading to withdrawal from further vaccination | An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. SAEs include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From Day 0 to Month 50 | 
| Number of subjects with severe malaria and cerebral malaria | Cerebral malaria is defined as Severe P. falciparum malaria with coma (Blantyre coma score score less than [<] 3); and if malaria with seizure: coma persisting for > 30 min after the seizure. Other treatable causes of coma should be excluded before diagnosing cerebral malaria (e.g. hypoglycaemia, bacterial meningitis). Severe malaria is defined as P. falciparum parasitemia > 0 detected by microscopy and/or rapid diagnostic test (RDT) and one or more of the following, occurring in the absence of an identified alternative cause: Impaired consciousness, Prostration, Multiple convulsions, Acidosis, Hypoglycemia, Severe malarial anemia, Renal impairment, Jaundice, Pulmonary edema, Significant bleeding: including recurrent or prolonged bleeding from the nose, gums or venipuncture sites, hematemesis or melaena, Shock, Hyperparasitemia. | From Day 0 to Month 50 | 
| Number of subjects with potential Immune mediated diseases (pIMDs) | Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune etiology. | From Day 0 to Month 50 | 
| Number of subjects with meningitis | The number of subjects with meningitis per study group. | From Day 0 to Month 50 | 
| Number of subjects with seizures | The number of subjects with seizures per study group. | During the 30-day (Days 0-29) follow-up period after each dose of study vaccine | 
| Number of subjects with generalized convulsive seizures | The number of subjects with generalized convulsive seizures per study group. | During the 7-day (Days 0-6) follow-up period after each dose of study vaccine | 
| Number of subjects with any unsolicited adverse events (AEs) | An unsolicited AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. | During the 30-day (Days 0-29) follow-up period after each dose of study vaccine | 
| Number of subjects with abnormal laboratory values (in a sub-cohort of first 25 subjects enrolled in each group per site) | The assessed parameters (alanine aminotransferase [ALT], creatinine, haemoglobin, white blood cells [WBC], platelets) will be summarised by toxicity grading scales and by group. | Before Dose 3, seven days post-Dose 3 and 30 days post-Dose 3 | 
| Number of subjects with any solicited local symptoms (in the reactogenicity sub-cohort of first 25 subjects enrolled per site) | Solicited local symptoms assessed will be pain, redness and swelling. | During the 4-day (Days 0-3) follow-up period after each vaccination | 
| Number of subjects with any solicited general symptoms (in the reactogenicity sub-cohort of first 25 subjects enrolled per site) | Solicited general symptoms assessed will be drowsiness, fever, irritability/fussiness and loss of appetite. | During the 4-day (Days 0-3) follow-up period after each vaccina-tion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
falciparum, efficacy, RTS,S/AS01, malaria vaccine, safety, Malaria, immunogenicity, infants