Pharmacy and Poisons Board: Applications

List Applications

Protocol No:

ECCT/09/09/02

Date of Protocol:

11-08-2009

Study Title:	*SAFETY AND IMMUNOGENICITY STUDY OF GSK BIOLOGICALS' Plasmondium falciparum* MALARIA VACCINE 257049 ADMINISTERED TO HIV INFECTED INFANTS AND CHILDREN**
Study Objectives:
Laymans Summary:
Abstract of Study:	The RTS,S/AS01E candidate malaria vaccine is being developed for the routine immunization of infants and children living in malaria-endemic areas. The RTS,S/AS01E candidate malaria vaccine consists of sequences of the ircumsporozoite (CS) protein and hepatitis B surface antigen (HBsAg) with the proprietary adjuvant AS01E (proprietary liposomes, MPL and Stimulon QS21 immunostimulants). The vaccine also induces a strong immune response against hepatitis B. In studies completed to date, the RTS,S candidate malaria vaccine adjuvanted with GSK’s proprietary Adjuvants systems has consistently demonstrated efficacy in the pediatric population in malaria endemic countries. It has a favorable safety profile when given to young children and infants in co-administration with EPI routine vaccines. In order for the RTS,S candidate vaccine to be recommended for vaccination in children and infants in sub-Saharan Africa, safety of the vaccine needs to be demonstrated in HIV positive children, given the HIV disease burden in some parts of Africa. Approximately 2-3 million children live with HIV in sub- Saharan Africa; about 1500 children are newly infected each day. Vertical transmission rates are approximately 12-40%, and down to 2% in the context of optimal Prevention of Mother-to-Child Transmission (PMCT). Although HIV infected children have defective immunity and low immune response to some vaccines, the WHO recommends that children who are, or are s uspected of being, infected with HIV but are not yet symptomatic should be given all vaccines as recommended by the national EPI program. It is only the BCG and, where applicable, yellow fever vaccine - two live attenuated vaccines - that are contra-indicated in children with symptomatic HIV infection, because of the risk of disseminated invasive disease post vaccination. In all other situations, benefits of vaccination by far outweigh any associated risk. For non-live vaccines, HIV infection has not been shown to be associated with an increased risk of adverse vaccine-related event. On the contrary, because of HIV-infected children’s susceptibility towards infections, vaccination is strongly advocated. As HIV infected children are more susceptible to malaria they may potentially gain additional benefits from receiving the malaria candidate vaccine. Among HIV-infected children up to 5 years of age, rates of parasitemia and parasite densities are higher than in those without HIV. HIV-infected infants are also at increased risk for severe anemia and for hospitalization due to malaria. Furthermore, malaria episodes can transiently increase viral load, and thus could theoretically have an impact on HIV disease progression and HIV transmission. This study will assess the safety and immunogenicity of the RTS,S/AS01E candidate malaria vaccine in HIV-infected infants and children. It will also describe the malaria experience, HIV viral load and CD4+ cell count of subjects. Through the monitoring of markers of HIV disease progression we will determine whether a reduction of malaria attacks in these children translates to a lower rate of HIV disease progression. We will also be able to exclude a potential detrimental effect of the vaccine on HIV disease progression. The clinical development of the RTS,S candidate malaria vaccine is conducted under a partnership agreement with the PATH Malaria Vaccine Initiative (MVI) and is guided by a joint MVI/GSK Steering Committee. This study is overseen by a formally constituted IDMC operating under a charter. Detailed Title A Phase III randomized, double blind (observer blinded), controlled study of the safety and immunogenicity of GlaxoSmithKline Biologicals’ candidate Plasmodium falciparum malaria vaccine RTS,S/AS01E (0.5 mL dose), administered IM according to a 0, 1, 2-month vaccination schedule in HIV infected infants and children living in a malaria-endemic region. Indication Primary immunization of HIV infected male and female infants and children (between and including 6 weeks and 17 months of age), if eligible according to inclusion and exclusion criteria. Rationale for the study and study design The RTS,S/AS01E candidate malaria vaccine is being developed for the routine immunization of infants and children living in malaria-endemic areas. The RTS,S/AS01E candidate malaria vaccine consists of sequences of the circumsporozoite (CS) protein and hepatitis B surface antigen (HBsAg) with the proprietary adjuvant AS01E (proprietary liposomes, MPL and Stimulon QS21 immunostimulants). The vaccine also induces a strong immune response against hepatitis B. In studies completed to date, the RTS,S candidate malaria vaccine adjuvanted with GSK’s proprietary Adjuvants Systems has consistently demonstrated efficacy in the pediatric population in malaria endemic countries. It has a favorable safety profile when given to young children and infants in co-administration with EPI routine vaccines. In order for the RTS,S candidate vaccine to be recommended for vaccination in children and infants in sub-Saharan Africa, safety of the vaccine needs to be demonstrated in HIV positive children, given the HIV disease burden in some parts of Africa. Approximately 2-3 million children live with HIV in sub- Saharan Africa; about 1500 children are newly infected each day. Vertical transmission rates are approximately 12-40%, and down to 2% in the context of optimal Prevention of Mother-to-Child Transmission (PMCT). Although HIV infected children have defective immunity and low immune response to some vaccines, the WHO recommends that children who are, or are suspected of being, infected with HIV but are not yet symptomatic should be given all vaccines as recommended by the national EPI program. It is only the BCG and, where applicable, yellow fever vaccine - two live attenuated vaccines - that are contra-indicated in children with symptomatic HIV infection, because of the risk of disseminated invasive disease post vaccination. In all other situations, benefits of vaccination by far outweigh any associated risk. For non-live vaccines, HIV infection has not been shown to be associated with an increased risk of adverse vaccine-related event. On the contrary, because of HIV-infected children’s susceptibility towards infections, vaccination is strongly advocated. As HIV infected children are more susceptible to malaria they may potentially gain additional benefits from receiving the malaria candidate vaccine. Among HIV-infected children up to 5 years of age, rates of parasitemia and parasite densities are higher than in those without HIV. HIV-infected infants are also at increased risk for severe anemia and for hospitalization due to malaria. Furthermore, malaria episodes can transiently increase viral load, and thus could theoretically have an impact on HIV disease progression and HIV transmission. This study will assess the safety and immunogenicity of the RTS,S/AS01E candidate malaria vaccine in HIV-infected infants and children. It will also describe the malaria experience, HIV viral load and CD4+ cell count of subjects. Through the monitoring of markers of HIV disease progression we will determine whether a reduction of malaria attacks in these children translates to a lower rate of HIV disease progression. We will also be able to exclude a potential detrimental effect of the vaccine on HIV disease progression. The clinical development of the RTS,S candidate malaria vaccine is conducted under a partnership agreement with the PATH Malaria Vaccine Initiative (MVI) and is guided by a joint MVI/GSK Steering Committee. This study is overseen by a formally constituted IDMC operating under a charter. Objectives *Primary: Safety*  To describe the safety (occurrence of SAEs) of RTS,S/AS01E when administered on a 0, 1, 2-month schedule to HIV-infected infants and children, until 14 months post Dose 1. Secondary :Safety  To describe the reactogenicity profile (occurrence of solicited symptoms) of RTS,S/AS01E when administered on a 0, 1, 2-month schedule to HIVinfected infants and children, during 7 days (day of vaccination and 6 subsequent days) after each vaccination.  To describe the safety (occurrence of unsolicited AEs) of RTS,S/AS01E when administered on a 0, 1, 2-month schedule to HIV-infected infants and children over a 30 day period after each vaccination.  To describe the occurrence of non-malaria-related SAEs in HIV infected infants and children vaccinated with RTS,S/AS01E when dministered on a 0, 1, 2-month schedule, until 14 months post Dose 1. Immunogenicity  To assess the antibody responses to CS and HBs antigens for RTS,S/AS01E when administered on a 0, 1, 2-month schedule to HIV-infected infants and children up to 12 months post Dose 3. Malaria monitoring  To monitor and describe the occurrence of malaria disease in HIV infected infants and children occurring during the study period. Progression of HIV disease  To describe the evolution of CD4+ cell counts (CD4 % and absolute counts), HIV viral load and HIV WHO clinical classification for RTS,S/AS01E when administered on a 0, 1, 2-month schedule to HIV-infected infants and children up to 14 months post Dose 1. Growth To describe growth in HIV infected infants and children during the study period. Study design  Experimental design: Phase III, double blind (observer blind), randomized (1:1 ratio) controlled trial with two groups, one vaccinated with the experimental malaria candidate vaccine RTS,S/AS01E, the other one with the rabies control vaccine.  Parents/Legally Acceptable Representatives (LARs) of HIV-infected infants and children will be identified at HIV clinics and will be informed about the study. If interested, and if the infant/child is eligible based on the inclusion and exclusion criteria, the parents/LARs will be asked to consent for study participation.  Route of vaccine administration: intramuscular (IM) route in the left antero-lateral thigh for infants < 5 months and left deltoid for infants/children  5 months of age.  The experimental vaccines will be given outside the context of co-administration with other vaccines. Standard EPI vaccine delivery will be allowed 1 week apart from study vaccines.  Each subject will be observed for at least 60 minutes after vaccination to evaluate and treat any acute adverse events (AEs).  There will be a 7-day follow-up period for solicited AEs post-vaccination. Day 0 evaluation will be carried out by the study clinician at the study center. Subsequently, trained field workers will visit the infants and children to solicit AEs on Days 1 to 5 after each vaccination. Evaluation on Day 6 post vaccination which will be carried out by the study clinician at the study center.  There will be a 30-day (day of vaccination and 29 subsequent days) follow-up after each vaccine dose for reporting unsolicited symptoms.  SAEs will be recorded throughout the study period. Prior to vaccination, any SAE due directly to study procedures will be recorded. All SAEs will be recorded beginning with the administration of the first dose and ending 14 months after the first dose of study vaccine. Monthly clinic visits will contribute to maximal capture of SAEs.  Safety blood samples for assessment of hematology, hepatic and renal function will be collected at baseline, 6 days post Dose 1, one month post Dose 3, 6 months post Dose 3 and 12 months post Dose 3. (Amended 26 January 2011).  IDMC reports: Safety reports will be sent at three time points after 30 subjects have completed the 7 days of follow-up post Dose 1, post Dose 2 and post Dose 3. The IDMC will review the data to authorize continuation of enrolment and vaccinations.  Long-lasting insecticide impregnated bednets and directions for use will be distributed at screening, regardless of the decision of parents/LARs to participate in the study or not.  Children and infants will be followed passively for the occurrence of clinical malaria for the duration of their participation in the study. Cases will be detected at all study health facilities.  P. falciparum parasitemia will be determined on a crosssectional sample in all study participants at study end (Month 14).  This study will be conducted in the context of access to an HIV management unit with availability of Voluntary Counseling and Testing (VCT),pediatric Highly Active Antiretroviral Therapy (HAART), daily trimethoprimsulfamethoxasole prophylaxis (co-trimoxazole: CTX) for the prevention of opportunistic infections, Prevention of Mother-to-Child Transmission (PMCT) and HIV clinical follow up, including immunology monitoring, according to the national HIV control guidelines. CTX prophylaxis and antiretroviral therapy (ART) will be monitored during the trial.  Subjects with Grade III or IV AIDS, with an acute illness resulting in deferment of vaccination past the 30-day window, or with an abnormal laboratory value at the time of enrolment will not be able to participate in the study (see exclusion criteria). However, in case the health of the subject improves, he or she might be re-onsidered for enrolment. In that case, a new ICF should be signed and all screening procedures should be repeated, except possibly the HIV DNA PCR test. (Amended 26 January 2011).  There will be a balanced randomization to ensure that both groups are comparable in terms of age and CD4 % levels. An equivalent number of children of age categories 6 weeks to 4 months and 5 months to 17 months, and with various CD4 % levels (<10%, 10-14%, 15-19%, 20%) will be enrolled in both study groups. Children can be enrolled whether or not they are on ART at enrollment. However all enrolled children will be provided ART and daily septrin, according to national guidelines.  Data collection: this study will use electronic case report forms (eCRF) by remote data entry (RDE).  Study duration will be approximately 14 months per subject.  The final analysis of the study will be conducted on all data collected up to Month 14 (Clinic Visit 19). Number of subjects 200 infants and children aged 6 weeks to 17 months will be enrolled. Primary endpoint :Safety  Serious adverse events Occurrence of SAEs from the time of first vaccination until 14 months post Dose 1. Secondary endpoints Safety  Solicited local and general symptoms Occurrence of general and local solicited symptoms over a 7-day follow-up period (day of vaccination and 6 subsequent days) after each vaccination.  Unsolicited adverse events Occurrence of unsolicited symptoms over a 30-day followup period (day of vaccination and 29 subsequent days) after each vaccination.  Non-malaria-related serious adverse events Occurrence of non-malaria-related SAEs from the time of first vaccination until 14 months post Dose 1. Immunogenicity  Immunogenicity of a primary course of investigational vaccine Anti-CS antibody titers prior to vaccination and one month post Dose 3. Anti-HBs antibody titers prior to vaccination and one month post Dose 3. Anti-CS antibody titers at 12 months post Dose 3. Anti-HBs antibody titers at 12 months post Dose 3. Malaria monitoring  Malaria disease:Occurrence of malaria disease according to specific case definitions.  Malaria parasitemia:Asexual P. falciparum parasitemia prevalence and density at 12 months post Dose 3. Progression of HIV disease  HIV viral load:Viral load (copies/mL) at baseline and at 1 month, 6 months and 12 months post Dose 3.  T-cell counts CD4+ % and absolute cell counts at baseline and at 1 month, 6 months and 12 months post Dose 3.  HIV clinical classification progression:WHO HIV clinical classification at baseline, 1 month, 6 months and 12 months post Dose 3. Growth  Growth parameters:Weight, age/length and middle upper arm circumference for age score at baseline and study end.