Clinical trial NCT00866619: Efficacy of GSK Biologicals' Candidate Malaria Vaccine 257049 Against Malaria Disease in Infants and Children in Africa
Official title: Efficacy of GSK Biologicals' Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. Falciparum Infection in Infants and Children in Africa
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: The PATH Malaria Vaccine Initiative (MVI)
First posted: 2009-03-20
Enrollment: 15459
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this observer-blind study is to gather key efficacy, safety, and immunogenicity information on GSK's candidate malaria vaccine in infants and children.

Detailed description: The protocol posting document has been updated due to a protocol amendment dated 23 January 2012. An analysis time point has been added at Month 20. No changes have been made to the protocol endpoints or statistical methods but protocol endpoints will be analysed on data collected up to Month 20 once these data are available. The rationale is to have the full scope of protocol defined efficacy and safety endpoints related to a primary schedule without booster in both age categories followed up for 20 months earlier than at the initially planned study end time point (Visit 34 or Month 32 time point).

The protocol posting document was updated due to a protocol amendment dated 10 December 2010 to extend the study until December 2013 for all enrolled subjects (interval: Nov 2013-Jan 2014). Including the extension, the mean follow-up time for subjects from 5-17 months will be during 49 months post dose 1 (range: 41-55), while for subjects from 6-12 weeks, it will be during 41 months post dose 1 (range: 32-48). This study is double-blind during the first part and single-blind during the extension part. An analysis will be conducted at the end of the extension including an evaluation of safety and efficacy against clinical malaria, severe malaria and prevalent parasitemia.

The protocol posting document has been updated following the posting of results of the study (January 2015): The study remained double-blind until the end of the extension phase, and the analyses of Month 32 (initial end of study now becoming end of the first part of the study or primary study phase) and of the extension phase were conducted together.

Eligibility criteria: Inclusion Criteria:

All subjects must satisfy the following criteria at study entry:

* A male or female child of:5-17 months (inclusive) of age at time of first vaccination,or between 6-12 weeks of age at time of first vaccination and NOT have already received a dose of vaccine against diphtheria, tetanus or pertussis or Hemophilus influenzae type B and must be \> 28 days of age at screening.
* Signed informed consent 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.

All subjects must satisfy the following criteria at the start of the extension phase:

* Subjects who were enrolled and who received at least one vaccine dose in the primary trial phase.
* Subjects who were present for Visit 35 on or before 30 September 2013.
* 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) should be enrolled in the study.

Exclusion Criteria:

The following criteria should be checked at the time of study entry. If any apply, the subject must not be included in the study:

* Acute disease at the time of enrollment.
* Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality.
* Anemia associated with clinical signs or symptoms of decompensation or hemoglobin ≥ 5.0 g/dL.
* Major congenital defects.
* History of allergic reactions, significant IgE-mediated events or anaphylaxis to previous immunizations.
* Children with a past history of a neurological disorder or atypical febrile seizure.
* Children with malnutrition requiring hospital admission.
* Children currently meeting the criteria for HIV disease of Stage III or Stage IV severity as defined by the World Health Organization.
* History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.
* Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to a drug or vaccine that is not licensed for that indication with the exception of studies with the objective of improving the drug treatment or clinical management of severe malaria disease.
* Use of a drug or vaccine that is not approved for that indication other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period.
* Previous participation in any other malaria vaccine trial.
* Receipt of a vaccine within the preceding 7 days.
* Any other findings that the investigator feels would increase the risk of having an adverse outcome from participation in the trial.
* Any other findings that the investigator feels would result in data collected being incomplete or of poor quality

Primary outcomes:
measure: Rate of First or Only Clinical Episode of Plasmodium Falciparum (P. Falciparum) Malaria Infection (CPFMI), or Clinical Malaria Episode of Primary Case Definition (CPFMI-PCD)
timeFrame: From Month 2.5 to Month 14
measure: Rate of First or Only Clinical Episode of P. Falciparum Malaria Infection (CPFMI), or Clinical Malaria Episode of Primary Case Definition (CPFMI-PCD)
timeFrame: From Month 2.5 to Month 14
Secondary outcomes:
measure: Rate of All Episodes of P. Falciparum Clinical Malaria Infection (CPFMI) of PCD and of Secondary Case Definitions (SCD) 1, SCD 2 and SCD 3
timeFrame: From Month 2.5 to Month 14
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of PCD, Overall and by Center
timeFrame: From Month 2.5 to Month 20
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of SCD1, SCD2 and SCD3 (Overall)
timeFrame: From Month 2.5 to Month 20
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Centers and Across Centers
timeFrame: From Month 2.5 up to study End (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Secondary Case Definition 1 (SCD1), Across Centers
timeFrame: From Month 2.5 up to study end (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD) and Secondary Case Definition 1 (SCD1), Across Centers
timeFrame: From Booster at Month 20 up to study end (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of PCD and SCD1, Across Centers
timeFrame: From Month 33 up to study end (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of PCD, by Center and Across Centers
timeFrame: From Month 2.5 to Month 32
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Secondary Case Definition 1 (SCD1)
timeFrame: From Month 2.5 to Month 32
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD) and Secondary Case Definition 1 (SCD1)
timeFrame: From Booster at Month 20 up to Month 32
measure: Percentage of Subjects With Severe PFMI (SPFMI) of PCD, SCD1, SCD2 and SCD3, Across Centers
timeFrame: From Month 2.5 up to the time when 250 subjects were diagnosed with severe malaria of PCD, SCD1, SCD2 and SCD3 (up to the Month 14 time point for each age category or date of booster dose, whichever occurred first)
measure: Percentage of Subjects With Severe PFMI (SPFMI) of PCD and SCD1
timeFrame: From Month 2.5 to Month 14
measure: Percentage of Subjects With Severe PFMI (SPFMI) of PCD and SCD1
timeFrame: From Month 2.5 to Month 20 at Booster
measure: Percentage of Subjects With Severe PFMI (SPFMI) of PCD and SCD1
timeFrame: From Month 2.5, from Month 20(booster), from Month 33 up to study end (median follow-up time of 48 months post-Dose 1 for 5-17M age category and of 38 months post-Dose 1 for 6-12W age category) and from Month 2.5 to Month 32 and from Month 20 to Month 32
measure: Percentage of Subjects With Incident Severe Anaemia (ISA) and Malaria Hospitalization (MH) for Case Definitions (CD) Considered
timeFrame: From Month 2.5 to Month 20
measure: Percentage of Subjects With Incident Severe Anaemia (ISA), Malaria Hospitalization (MH) and Fatal Malaria (FM) for Case Definitions (CD) Considered
timeFrame: From Month 2.5 to up to study end (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)
measure: Percentage of Subjects With Incident Severe Anaemia (ISA), Malaria Hospitalization (MH) and Fatal Malaria (FM) for Case Definitions (CD) Considered
timeFrame: From Month 2.5 to Month 32
measure: Percentage of Subjects With Prevalent Parasitemia, Prevalent Gametocytemia and Prevalent Severe and Moderate Anemia
timeFrame: At Month 20 (Booster)
measure: Percentage of Subjects With Prevalent Parasitemia and Prevalent Severe and Moderate Anemia
timeFrame: At Months 32, 44, at study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category) (early and late)
measure: Percentage of Subjects With Pneumonia, All-cause Hospitalization and Sepsis, as Per Case Definitions Assessed
timeFrame: From Month 2.5 to Month 20
measure: Percentage of Subjects With Fatal Malaria (FM) and All-cause Mortality (ACM) as Per Case Definitions Assessed
timeFrame: From Month 2.5 to Month 20
measure: Percentage of Subjects With Pneumonia, All-cause Hospitalization/Mortality and Sepsis, as Per Case Definitions Assessed
timeFrame: From Month 2.5 up to study end (with a median follow-up time post-Dose 1 of 48 months for 5-17M groups and 38 months for 6-12W groups)
measure: Percentage of Subjects With Blood Transfusion, as Per Case Definition Assessed
timeFrame: From Month 2.5 up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Gender and Overall
timeFrame: From Month 2.5 to Month 32
measure: Height, Weight and Mid Upper Arm Circumference for Age Z-score (HAZ, WAZ and MUACZ)
timeFrame: At Month 20 (Booster)
measure: Height, Weight and Mid Upper Arm Circumference for Age Z-score (HAZ, WAZ and MUACZ)
timeFrame: At Months 32, 44, at study end (early and late) (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)
measure: Antibody Concentrations Against Plasmodium Falciparum Circumsporozoite (Anti-CS)
timeFrame: At Day 0 and at Month 3
measure: Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS)
timeFrame: At Day 0 and at Month 3
measure: Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS)
timeFrame: At Months 20, 21 and 32
measure: Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS)
timeFrame: At Month 44 and at study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)
measure: Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS), by Tertile
timeFrame: At Month 3
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Tertile
timeFrame: From Month 2.5 to Month 32
measure: Antibody Concentrations Against P. Falciparum Circumsporozoite (Anti-CS), by Tertile
timeFrame: At Month 21
measure: Rate of All Episodes of Clinical P. Falciparum Malaria Infection (CPFMI) of Primary Case Definition (PCD), by Tertile
timeFrame: From Booster at Month 20 to Month 32
measure: Antibody Concentrations Against Hepatitis B Surface Antigen (Anti-HBs)
timeFrame: At Day 0 and at Month 3
measure: Antibody Concentrations Against Hepatitis B Surface Antigen
timeFrame: At Day 0 and at Month 3
measure: Antibody Concentrations Against Hepatitis B Surface Antigen (Anti-HBs)
timeFrame: At Months 20 and 21
measure: Antibody Titers Against Poliomyelitis (Anti-polio) Type 1, 2 and 3
timeFrame: At Day 0 and at Month 3
measure: Number of Subjects With Any and Grade 3 Solicited Local Symptoms
timeFrame: During the 7-day (Days 0-6) post-primary vaccination period following each dose and across doses
measure: Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms
timeFrame: During the 7-day (Days 0-6) post-primary vaccination period following each dose and across doses
measure: Number of Subjects With Any and Grade 3 Solicited Local Symptoms
timeFrame: During the 7-day (Days 0-6) post-booster vaccination period
measure: Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms
timeFrame: During the 7-day (Days 0-6) post-booster vaccination period
measure: Number of Doses With Seizures by Diagnostic Certainty Level
timeFrame: During the 7-day (Days 0-6) post-booster vaccination period, at Month 20 + 7 Day (Days 0-6)
measure: Number of Subjects Reporting Mucocutaneous Changes (All Levels)
timeFrame: During the 30-day (Days 0-29) post-booster vaccination
measure: Number of Subjects Reporting Any Meningitis and Encephalitis Serious Adverse Events (SAEs)
timeFrame: At Month 0 until study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)
measure: Number of Subjects Reporting Any Meningitis and Encephalitis SAEs
timeFrame: From Booster up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)
measure: Number of Subjects Reporting Any Potential Immune-mediated Disorders (pIMDs)
timeFrame: From Month 0 up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)
measure: Number of Subjects With Any Unsolicited Adverse Events (AEs)
timeFrame: Within the 30-day (Days 0-29) post-primary vaccination period
measure: Number of Subjects With Unsolicited AEs Related to or Leading to Vaccination Withdrawal
timeFrame: Within the 30-day (Days 0-29) post-primary vaccination period
measure: Number of Subjects With Any Unsolicited AEs
timeFrame: Within the 30-day (days 0-29) post-booster vaccination period
measure: Number of Subjects With Unsolicited AEs Related to or Leading to Vaccination Withdrawal
timeFrame: Within the 30-day (Days 0-29) post-primary and post-booster vaccination period in HIV-infected children
measure: Number of Subjects With Unsolicited AEs Related to or Leading to Vaccination Withdrawal in the Low-weight (LW) and Very Low-weight (VLW) Category
timeFrame: Within the 30-day (Days 0-29) post-primary vaccination period in HIV-infected children
measure: Number of Subjects With Unsolicited AEs Related to Vaccination in the Low-weight (LW) and Very Low-weight (VLW) Category
timeFrame: Within the 30-day (Days 0-29) post-booster vaccination period
measure: Number of Subjects With Serious Adverse Events (SAEs)
timeFrame: From Month 0 up to Month 14
measure: Number of Subjects With Serious Adverse Events (SAEs)
timeFrame: During the 30-day (Days 0-29) post-primary vaccination period
measure: Number of Subjects With Serious Adversee Events (SAEs)
timeFrame: From Month 0 up to Month 20
measure: Number of Subjects With Serious Adverse Events (SAEs)
timeFrame: From Booster (at Month 20) up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)
measure: Number of Subjects With Serious Adverse Events (SAEs)
timeFrame: From Month 0 up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)
measure: Number of Subjects With Serious Adverse Events (SAEs)
timeFrame: Within the 30-day (Days 0-29) post-booster vaccination period
measure: Number of Subjects With Serious Adverse Events (SAEs)
timeFrame: From Month 0 up to Booster (Month 20), from Month 0 up to study end and from Month 20 up to study end
measure: Number of Low-weight (LW) Subjects With Serious Adverse Events (SAEs)
timeFrame: From Month 0 up to Month 20
measure: Number of Low-weight (LW) Subjects With Serious Adverse Events (SAEs)
timeFrame: From Booster (Month 20) up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)
measure: Number of Very Low-weight (VLW) Subjects With Serious Adverse Events (SAEs)
timeFrame: From Month 0 up to Month 20
measure: Number of Very Low-weight Subjects With Serious Adverse Events (SAEs)
timeFrame: From Booster (Month 20) up to study end (median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)]
measure: Number of Subjects With Fatal Outcomes, by Gender
timeFrame: From Month 0 up to study end (SE - median follow-up time of 48 months post-Dose 1 for 5-17 months age category and of 38 months post-Dose 1 for 6-12 weeks age category)
Other outcomes:
Locations:
city: Ouagadougou
country: Burkina Faso
facility: GSK Investigational Site
city: Lambaréné
country: Gabon
facility: GSK Investigational Site
city: Kintampo
country: Ghana
facility: GSK Investigational Site
city: Kumasi
country: Ghana
facility: GSK Investigational Site
city: Kilifi
country: Kenya
facility: GSK Investigational Site
city: Kisumu
country: Kenya
facility: GSK Investigational Site
city: Lilongwe
country: Malawi
facility: GSK Investigational Site
city: Maputo
country: Mozambique
facility: GSK Investigational Site
city: Dar-es-Salaam
country: Tanzania
facility: GSK Investigational Site
city: Tanga
country: Tanzania
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
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