Clinical trial NCT03276962: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malaria
Keywords: falciparum, efficacy
RTS,S/AS01
malaria vaccine
safety
Malaria
immunogenicity
infants
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-09-08
Enrollment: 1500
Sex: ALL
Minimum age (years): 5
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: Inclusion Criteria:

* Participants' 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 participant 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 participants 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 participants) 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 participant 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 participants with 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.

Participants 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.

Primary outcomes:
measure: Incidence of Clinical Malaria Meeting the Primary Case Definition
timeFrame: From Month 2.5 to Month 14
Secondary outcomes:
measure: Incidence of Clinical Malaria Meeting the Primary and Secondary Case Definitions of the Fx012-14-mFxD Group Versus the R012-20 Group
timeFrame: From Month 0 to Month 50
measure: Incidence of Clinical Malaria Meeting the Primary and Secondary Case Definitions of the Fx012-14-mFxD Group Versus the R012-14-mD Group
timeFrame: From Month 0 to Month 50
measure: The Prevalence of P. Falciparum Infections Defined by Positive Blood Slide at Each Cross-sectional Survey
timeFrame: Monthly from Month 0 to Month 20 and every 3 months thereafter until Study End (Month 50)
measure: Incidence of P. Falciparum Infections Defined by Positive Blood Slide
timeFrame: Month 0 to Month 14
measure: Number of Seropositive Participants for Anti-circumsporozoite (Anti-CS) Antibodies
timeFrame: Before Dose 1, one month post-Dose 2, 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)
measure: Number of Seropositive Participants for Anti-hepatitis B (Anti-HB) Antibodies
timeFrame: Before Dose 1, one month post-Dose 2, 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)
measure: Antibody Concentrations for Anti-CS
timeFrame: Before Dose 1, one month post-Dose 2, 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)
measure: Antibody Concentrations for Anti-HB
timeFrame: Before Dose 1, one month post-Dose 2, 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)
measure: Number of Participants With Any, Fatal and Related Serious Adverse Events (SAEs)
timeFrame: From Day 0 to Month 50
measure: Number of Participants With Any Adverse Events (AEs) and SAEs Leading to Withdrawal From Further Vaccination
timeFrame: From Day 0 to Month 50
measure: Number of Participants With Cerebral Malaria and Severe Malaria
timeFrame: From Day 0 to Month 50
measure: Number of Participants With Potential Immune Mediated Diseases (pIMDs)
timeFrame: From Day 0 to Month 50
measure: Number of Participants With Meningitis
timeFrame: From Day 0 to Month 50
measure: Number of Participants With Seizures
timeFrame: During the 30-day (Day 0 to Day 29) follow-up period after any dose of study vaccine
measure: Number of Participants With Generalized Convulsive Seizures
timeFrame: During the 7-day (Day 0 to Day 6) follow-up period after any dose of study vaccine
measure: Number of Participants With Any Unsolicited AEs
timeFrame: During the 30-day (Day 0 to Day 29) follow-up period following the 1st 3 doses and post dose 4, 5 and 6 of study vaccine
measure: Number of Participants With Grade 4 Hematology and Biochemical Toxicities Before Dose 3
timeFrame: Before Dose 3 (at Month 2)
measure: Number of Participants With Grade 4 Hematology and Biochemical Toxicities at 7 Days Post-Dose 3
timeFrame: At 7 days post-Dose 3
measure: Number of Participants With Grade 4 Hematology and Biochemical Toxicities at 30 Days Post-Dose 3
timeFrame: At 30 days post-Dose 3
measure: Number of Participants With Any Solicited Local Symptoms
timeFrame: During the 4-day (Day 0 to Day 3) follow-up period after Dose 3, Dose 4, Dose 5 and Dose 6 of study vaccination
measure: Number of Participants With Any Solicited General Symptoms
timeFrame: During the 4-day (Day 0 to Day 3) follow-up period after Dose 3, Dose 4, Dose 5 and Dose 6 of study vaccination
Other outcomes:
Locations:
city: Kumasi
country: Ghana
facility: GSK Investigational Site
city: Kisumu
country: Kenya
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Westercamp N, Osei-Tutu L, Schuerman L, Kariuki SK, Bollaerts A, Lee CK, Samuels AM, Ockenhouse C, Bii DK, Adjei S, Oneko M, Lievens M, Attobrah Sarfo MA, Atieno C, Bakari A, Sang T, Kotoh-Mortty MF, Otieno K, Roman F, Buabeng PBY, Ntiamoah Y, Ansong D, Agbenyega T, Ofori-Anyinam O. Could Less Be More? Accounting for Fractional-Dose Regimens and Different Number of Vaccine Doses When Measuring the Impact of the RTS,S/AS01E Malaria Vaccine. J Infect Dis. 2024 Aug 16;230(2):e486-e495. doi: 10.1093/infdis/jiae075.
citation: Samuels AM, Ansong D, Kariuki SK, Adjei S, Bollaerts A, Ockenhouse C, Westercamp N, Lee CK, Schuerman L, Bii DK, Osei-Tutu L, Oneko M, Lievens M, Attobrah Sarfo MA, Atieno C, Morelle D, Bakari A, Sang T, Jongert E, Kotoh-Mortty MF, Otieno K, Roman F, Buabeng PBY, Ntiamoah Y, Ofori-Anyinam O, Agbenyega T; RTS,S study group. Efficacy of RTS,S/AS01E malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5-17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trial. Lancet Infect Dis. 2022 Sep;22(9):1329-1342. doi: 10.1016/S1473-3099(22)00273-0. Epub 2022 Jun 23.