Clinical trial NCT00380393: Efficacy of RTS,S/AS01 Vaccine Against Episodes of Malaria Due to P. Falciparum Infection in Children.
Official title: A Study of the Efficacy Against Episodes of Clinical Malaria Due to P. Falciparum Infection of GSK Biologicals Candidate Vaccine RTS,S/AS01, Administered According to a 0,1,2-months Schedule in Children Aged 5 to 17 Months Living in Tanzania & Kenya
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malaria
Keywords: Malaria
Plasmodium
RTS
S/AS01
Falciparum
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2006-09-26
Enrollment: 894
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: This phase IIb trial is being done to find out if the RTS,S/AS01 vaccine helps to prevent children from falling ill with malaria and to evaluate vaccine safety.

The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.


Eligibility criteria: Inclusion Criteria:

* A male or female child of between 5 months and 17 months 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.

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 for haemoglobin, total white cell count, platelets, ALT and creatinine out of acceptable limits.
* Planned administration/administration of a vaccine not foreseen by the study within 30 days of the first dose of vaccine(s) with the exception of tetanus toxoid or scheduled diphtheria, pertussis or measles vaccine.
* 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 (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within 6 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.
* 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.

Primary outcomes:
measure: Frequency of First Case of Malaria Meeting the Primary Case Definition
timeFrame: Assessed over average of 7.8 months post Dose 3 (range 4.3 to 10.3 months)
Secondary outcomes:
measure: Frequency of First Case Malaria Meeting the Secondary Case Definition
timeFrame: Assessed over average of 7.8 months post Dose 3 (range 4.3 to 10.3 months)
measure: Multiple Events of Malaria Meeting the Primary Case Definition
timeFrame: Assessed over average of 7.8 months post Dose 3 (range 4.3 to 10.3 months)
measure: Multiple Events of Malaria Meeting the Secondary Case Definition
timeFrame: Assessed over average of 7.8 months post Dose 3 (range 4.3 to 10.3 months)
measure: Number of Subjects Positive for P. Falciparum Parasitaemia
timeFrame: At the Cross-Sectional Visit that took place for each participant at on average 7.8 months post Dose 3 (range 4.3 to 10.3 months)
measure: Geometric Mean Density of Asexual P. Falciparum Parasite
timeFrame: At the Cross-Sectional Visit that took place for each participant at on average 7.8 months post Dose 3 (range 4.3 to 10.3 months)
measure: Haemoglobin Values at Cross-Sectional Visit
timeFrame: At the Cross-Sectional Visit that took place for each participant at on average 7.8 months post Dose 3 (range 4.3 to 10.3 months)
measure: Number of Subjects With Any and Grade 3 Solicited Local Symptoms
timeFrame: During the 7-day (Days 0-6) post-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-vaccination period following each dose and across doses
measure: Number of Subjects With Any Unsolicited Adverse Events (AEs)
timeFrame: Within the 30-day (Days 0-29) post-vaccination follow-up period
measure: Number of Subjects With Serious Adverse Events (SAEs)
timeFrame: Throughout the study period (Day 0 - Month 14)
measure: Number of Subjects With Hemoglobin Values Outside Normal Ranges With Toxicity Grades
timeFrame: At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29)
measure: Number of Subjects With White Blood Cell (WBC) Values Outside Normal Ranges With Toxicity Grades
timeFrame: At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29)
measure: Number of Subjects With Platelet Values Outside Normal Ranges With Toxicity Grades
timeFrame: At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29)
measure: Number of Subjects With Alanine Aminotransferase (ALT) Values Outside Normal Ranges With Toxicity Grades
timeFrame: At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29)
measure: Number of Subjects With Creatinine Values Outside Normal Ranges With Toxicity Grades
timeFrame: At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29)
measure: Concentration of Antibodies Against the P. Falciparum Circumsporozoite (CS) Repeat Domain (Anti-CS)
timeFrame: At Day 0, Month 3 and at Cross-sectional Visit (took place between 7 and 13 months post Dose 1, mean: 10 months, standard deviation: 1.29)
measure: Concentration of Antibodies Against Hepatitis B Surface Antigen (Anti-HBs)
timeFrame: At Day 0 and at Month 3
measure: Frequency of Cluster of Differentiation 4 (CD4+) CS-specific T-cells
timeFrame: Prior to vaccination (Day 0)
measure: Frequency of Cluster of Differentiation 8 (CD8+) CS-specific T-cells
timeFrame: Prior to vaccination (Day 0)
measure: Frequency of Cluster of Differentiation 4 (CD4+) CS-specific T-cells
timeFrame: At Month 3
measure: Frequency of Cluster of Differentiation 8 (CD8+) CS-specific T-cells
timeFrame: At Month 3
Other outcomes:
Locations:
city: Kilifi
country: Kenya
facility: GSK Investigational Site
city: Amani, Tanga
country: Tanzania
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Bejon P, Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Mshamu S, Lang T, Gould J, Dubois MC, Demoitie MA, Stallaert JF, Vansadia P, Carter T, Njuguna P, Awuondo KO, Malabeja A, Abdul O, Gesase S, Mturi N, Drakeley CJ, Savarese B, Villafana T, Ballou WR, Cohen J, Riley EM, Lemnge MM, Marsh K, von Seidlein L. Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N Engl J Med. 2008 Dec 11;359(24):2521-32. doi: 10.1056/NEJMoa0807381. Epub 2008 Dec 8.
citation: Lang TA, Gould J, von Seidlein L, Lusingu JP, Mshamu S, Ismael S, Liheluka E, Kamuya D, Mwachiro D, Olotu A, Njuguna P, Bejon P, Marsh V, Molyneux C. Approaching the community about screening children for a multicentre malaria vaccine trial. Int Health. 2012 Mar;4(1):47-54. doi: 10.1016/j.inhe.2011.10.003.
citation: Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Olivier A, Benns S, Olomi R, Msham S, Lang T, Gould J, Hallez K, Guerra Y, Njuguna P, Awuondo KO, Malabeja A, Abdul O, Gesase S, Dekker D, Malle L, Ismael S, Mturi N, Drakeley CJ, Savarese B, Villafana T, Ballou WR, Cohen J, Riley EM, Lemnge MM, Marsh K, Bejon P, von Seidlein L. Safety of the malaria vaccine candidate, RTS,S/AS01E in 5 to 17 month old Kenyan and Tanzanian Children. PLoS One. 2010 Nov 29;5(11):e14090. doi: 10.1371/journal.pone.0014090.
citation: Olotu A, Lusingu J, Leach A, Lievens M, Vekemans J, Msham S, Lang T, Gould J, Dubois MC, Jongert E, Vansadia P, Carter T, Njuguna P, Awuondo KO, Malabeja A, Abdul O, Gesase S, Mturi N, Drakeley CJ, Savarese B, Villafana T, Lapierre D, Ballou WR, Cohen J, Lemnge MM, Peshu N, Marsh K, Riley EM, von Seidlein L, Bejon P. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect Dis. 2011 Feb;11(2):102-9. doi: 10.1016/S1473-3099(10)70262-0. Epub 2011 Jan 13.
citation: Olotu A, Clement F, Jongert E, Vekemans J, Njuguna P, Ndungu FM, Marsh K, Leroux-Roels G, Bejon P. Avidity of anti-circumsporozoite antibodies following vaccination with RTS,S/AS01E in young children. PLoS One. 2014 Dec 15;9(12):e115126. doi: 10.1371/journal.pone.0115126. eCollection 2014.
citation: Warimwe GM, Fletcher HA, Olotu A, Agnandji ST, Hill AV, Marsh K, Bejon P. Peripheral blood monocyte-to-lymphocyte ratio at study enrollment predicts efficacy of the RTS,S malaria vaccine: analysis of pooled phase II clinical trial data. BMC Med. 2013 Aug 21;11:184. doi: 10.1186/1741-7015-11-184.
citation: Horowitz A, Hafalla JC, King E, Lusingu J, Dekker D, Leach A, Moris P, Cohen J, Vekemans J, Villafana T, Corran PH, Bejon P, Drakeley CJ, von Seidlein L, Riley EM. Antigen-specific IL-2 secretion correlates with NK cell responses after immunization of Tanzanian children with the RTS,S/AS01 malaria vaccine. J Immunol. 2012 May 15;188(10):5054-62. doi: 10.4049/jimmunol.1102710. Epub 2012 Apr 13.