Ignite Creation Date:
2024-10-26 @ 3:43 PM
Last Modification Date:
2024-10-26 @ 3:43 PM
Study NCT ID:
NCT06652737
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-18
Brief Title:
Age De-escalation Safety Trial of PfSPZ-LARC2 Vaccine in Burkina Faso
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Age De-escalation Clinical Trial to Evaluate the Safety Tolerability and Immunogenicity of a Late Liver Stage-arresting Replication-competent Plasmodium Falciparum Sporozoite Vaccine Sanaria PfSPZ-LARC2 Vaccine Administered by Direct Venous Inoculation to Malaria-exposed Adults Children and Infants in Burkina Faso
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a first-in-humans randomized double-blind placebo-controlled Phase 1 trial of Plasmodium falciparum Pf late liver stage-arresting replication-competent LARC sporozoite SPZ malaria vaccine PfSPZ-LARC2 Vaccine administered to healthy malaria-exposed adults children and optionally infants by direct venous inoculation DVI to determine safety tolerability and immunogenicity The PfSPZ comprising PfSPZ-LARC2 Vaccine contain a double genetic deletion of the Mei2 and LINUP genes and undergo developmental arrest in the late liver stages without releasing merozoites into the blood stream no blood stage parasites are produced Because Pf parasites with the LARC phenotype replicate in the liver they are expected to be a potent immunogen to induce anti-malarial immunity similar to replication-competent chemo-attenuated Sanaria PfSPZ-CVac chloroquine Because the parasites are also intrinsically attenuated they are expected to be highly safe and well tolerated similar to radiation-attenuated Sanaria PfSPZ Vaccine and to the single-geneMei2-deleted GA2 vaccine also LARC phenotype tested at the Leiden University Medical Center The genetically attenuated PfSPZ-LARC2 Vaccine should thus combine the best-in-class efficacy of PfSPZ-CVac chloroquine with the excellent safety and tolerability of intrinsically attenuated PfSPZ Vaccine and GA2 vaccine
This trial is designed to test the hypotheses that
1 The vaccine is safe and well tolerated in each age groups
2 The true rate of breakthrough blood stage infection or other concerning adverse events is less than about 5 with an 95 confidence level this will be the level of confidence that there are no breakthroughs if no breakthroughs occur in the 60 participants receiving PfSPZ-LARC2 Vaccine
This trial is designed to test the hypotheses that
1 The vaccine is safe and well tolerated in each age groups
2 The true rate of breakthrough blood stage infection or other concerning adverse events is less than about 5 with an 95 confidence level this will be the level of confidence that there are no breakthroughs if no breakthroughs occur in the 60 participants receiving PfSPZ-LARC2 Vaccine
Detailed Description:
This is a randomized double-blind placebo-controlled single-center Phase 1 clinical trial The dose of PfSPZ will be 20x105 the same as the dose used in an NIH study which resulted in 100 vaccine efficacy against a heterologous controlled human malaria infection CHMI conducted 12 weeks after immunization which represents the best protection ever recorded for a malaria vaccine However in the initial adult group 15 participants will be administered three times this dose - 60x105 PfSPZ - to assess the risk of breakthrough more stringently in a malaria-experienced adult population who are at low risk for serious complications of malaria infection If this high dose does not break through in adults it is unlikely that a 3-fold smaller dose will break through in children
Each group will be composed of 15 participants 10 to receive PfSPZ-LARC2 Vaccine and 5 to receive normal saline NS placebo with randomized blinded 21 allocation to vaccine and placebo in each group As the core of the study there will be three cohorts of participants initiated in staggered fashion 2 groups in cohort 1 followed by 2 groups in cohort 2 followed by 1 group in cohort 3 with Safety Monitoring Committee SMC review of safety and tolerability before proceeding to the next cohort Each group will begin with a pilot group of 2 vaccinees and 1 placebo recipient three days before the rest of the cohort initiates as a safety precaution
Cohort 1 Group 1 20-50-year-olds 15 participants receive single injection of 20x105 PfSPZ or NS
Group 2 20-50-year-olds 15 participants receive single injection of 60x105 PfSPZ or NS
Cohort 2 Group 3 11-19-year-olds 15 participants receive single injection of 20x105 PfSPZ or NS
Group 4 6-10-year-olds 15 participants receive single injection of 20x105 PfSPZ or NS
Cohort 3 Group 5 1-5-year-olds 15 participants receive three 4-weekly injections of 20x105 PfSPZ or NS
In addition to these three cohorts there is an optional fourth cohort consisting of infants This will be included if resources are adequate and if the safety data from the first three cohorts when reviewed by the SMC is deemed supportive of progressing to infants
Cohort 4 optional Group 6 5-11-month-olds 15 participants receive single injection of 20x105 PfSPZ or NS
Total sample size 15 x 5 75 participants if Group 6 included 90 participants
SMC meetings will be scheduled to review safety and parasitology data collected for two weeks after each dose in cohorts 1-3 If there are no vaccine strain breakthrough infections in a given cohort cohorts 1-3 and if the vaccine is well-tolerated the SMC will be asked to consider recommending proceeding to the next cohort cohorts 2-4 If there are vaccine strain breakthroughs the trial may continue on SMC recommendation but the restructured trial design will require IRB review and approval
Note that there are three doses planned for Group 5 in the third cohort - the target pre-school population for the Phase 2 trial described above These are included in case unexpectedly the adverse event profile after the second or third doses differs from after the first
Participants will be followed for parasitemia by TBS and for solicited and unsolicited adverse events after immunization TBS to monitor for Pf blood stage infections will be performed every two days from Day 7 day 6 to Day 19 day 18 and then on Days 21 24 and 29 days 20 23 and 28 In addition to TBS follow-up samples will be obtained at key timepoints for retrospective qPCR Retrospective qPCR will be performed if there is a scientific need However the qPCR using the samples collected on day 28 after the last immunization will be performed on all participants to document that no parasite is present in the blood at the end of active follow-up
Additional TBS will be performed when clinically indicated This includes 1 when a study participant develops a fever axillary temperature in adults 375C 995F or tympanic temperature in children of 380C 1004F and symptoms suggestive of malaria or 2 the investigator perceives for any reason a need for a rapid evaluation
Any density of parasitemia identified by TBS will be considered indicative of malaria infection and will be treated after a sample is obtained to allow genomic analysis of the parasite to determine if it is vaccine strain or wild-type Pf infection
Solicited and unsolicited adverse events will be recorded for 28 days after each immunization and serious adverse events SAEs will be monitored throughout the trial Laboratory tests will be done pre-immunization day of vaccination and one and four weeks after the immunization complete blood count creatinine aspartate aminotransferase alanine aminotransferase
Three and six months after the final immunization there will be a follow-up visit to ascertain the participants health
Definition of blood stage parasitemia during the immunization phase Any positive TBS showing normal appearing parasites confirmed by a second reader with a third reader used to resolve disagreements between the first two
If the TBS turns positive during follow-up If a participant develops parasitemia they will be treated as soon as parasitemia is identified even if asymptomatic A blood sample adequate for genetic analysis required and culture optional will be obtained by venipuncture prior to treatment The drugs for treatment will be dihydroartemisinin-piperaquine DHAP or artemether-lumefantrine AL In addition any participant shown to have a breakthrough LARC2 parasite will be administered a single low dose of primaquine to kill any gametocytes and prevent transmission
Genetic analyses will be performed to determine whether the parasite is the vaccine strain or a wild type naturally acquired Pf strain If it is a wild type parasite the trial will continue without SMC consultation If the parasite is vaccine strain the Sponsor will be notified and the SMC consulted with regard to measures required to assure safety of the participants
Clearance of parasitemia prior to immunization Because the study is being done in malaria-exposed individuals some of whom may have chronic parasitemia it will be important to clear any existing parasitemia prior to immunization Otherwise these pre-existing parasitemias could recrudesce during follow-up confusing the ability to identify breakthroughs Clearance will be administered to all participants because it is not possible to determine which participants have latent infection even if the most sensitive PCR is used Clearance will be done using a full treatment course of atovaquone-proguanil AP with dosing adjusted for agebody weight and using directly observed treatment DOT This drug combination is selected based on the relatively short half-lives of the drugs compared to artemisinin combination therapies A short half-life is needed so that the drug does not interfere with the detection of any breakthrough parasitemias post immunization If possible the study will be performed in a location or during a period of the year when transmission levels are low However if naturally acquired parasitemia occurs during immunization and follow-up it will be possible to distinguish these parasites from the PfNF54 strain that comprises the vaccine by genetic analysis based on PCR as described
Clearance of parasitemia four weeks after immunization As a safety precaution all individuals will be treated again four weeks after immunization DHA-P or AL will be used as there is no concern about drug half-lives in this case
Long-term Follow-up Participants or their parents will be contacted at 3 months and 6 months to obtain follow-up recording any episodes of clinical malaria or unexplained SAEs Clinical malaria that is not identified by the study team and reported historically by parents guardians or participants will be defined as a positive diagnostic test TBS or rapid diagnostic test plus fever as defined previously plus symptoms consistent with malaria Any such individual will have a blood smear examined
Each group will be composed of 15 participants 10 to receive PfSPZ-LARC2 Vaccine and 5 to receive normal saline NS placebo with randomized blinded 21 allocation to vaccine and placebo in each group As the core of the study there will be three cohorts of participants initiated in staggered fashion 2 groups in cohort 1 followed by 2 groups in cohort 2 followed by 1 group in cohort 3 with Safety Monitoring Committee SMC review of safety and tolerability before proceeding to the next cohort Each group will begin with a pilot group of 2 vaccinees and 1 placebo recipient three days before the rest of the cohort initiates as a safety precaution
Cohort 1 Group 1 20-50-year-olds 15 participants receive single injection of 20x105 PfSPZ or NS
Group 2 20-50-year-olds 15 participants receive single injection of 60x105 PfSPZ or NS
Cohort 2 Group 3 11-19-year-olds 15 participants receive single injection of 20x105 PfSPZ or NS
Group 4 6-10-year-olds 15 participants receive single injection of 20x105 PfSPZ or NS
Cohort 3 Group 5 1-5-year-olds 15 participants receive three 4-weekly injections of 20x105 PfSPZ or NS
In addition to these three cohorts there is an optional fourth cohort consisting of infants This will be included if resources are adequate and if the safety data from the first three cohorts when reviewed by the SMC is deemed supportive of progressing to infants
Cohort 4 optional Group 6 5-11-month-olds 15 participants receive single injection of 20x105 PfSPZ or NS
Total sample size 15 x 5 75 participants if Group 6 included 90 participants
SMC meetings will be scheduled to review safety and parasitology data collected for two weeks after each dose in cohorts 1-3 If there are no vaccine strain breakthrough infections in a given cohort cohorts 1-3 and if the vaccine is well-tolerated the SMC will be asked to consider recommending proceeding to the next cohort cohorts 2-4 If there are vaccine strain breakthroughs the trial may continue on SMC recommendation but the restructured trial design will require IRB review and approval
Note that there are three doses planned for Group 5 in the third cohort - the target pre-school population for the Phase 2 trial described above These are included in case unexpectedly the adverse event profile after the second or third doses differs from after the first
Participants will be followed for parasitemia by TBS and for solicited and unsolicited adverse events after immunization TBS to monitor for Pf blood stage infections will be performed every two days from Day 7 day 6 to Day 19 day 18 and then on Days 21 24 and 29 days 20 23 and 28 In addition to TBS follow-up samples will be obtained at key timepoints for retrospective qPCR Retrospective qPCR will be performed if there is a scientific need However the qPCR using the samples collected on day 28 after the last immunization will be performed on all participants to document that no parasite is present in the blood at the end of active follow-up
Additional TBS will be performed when clinically indicated This includes 1 when a study participant develops a fever axillary temperature in adults 375C 995F or tympanic temperature in children of 380C 1004F and symptoms suggestive of malaria or 2 the investigator perceives for any reason a need for a rapid evaluation
Any density of parasitemia identified by TBS will be considered indicative of malaria infection and will be treated after a sample is obtained to allow genomic analysis of the parasite to determine if it is vaccine strain or wild-type Pf infection
Solicited and unsolicited adverse events will be recorded for 28 days after each immunization and serious adverse events SAEs will be monitored throughout the trial Laboratory tests will be done pre-immunization day of vaccination and one and four weeks after the immunization complete blood count creatinine aspartate aminotransferase alanine aminotransferase
Three and six months after the final immunization there will be a follow-up visit to ascertain the participants health
Definition of blood stage parasitemia during the immunization phase Any positive TBS showing normal appearing parasites confirmed by a second reader with a third reader used to resolve disagreements between the first two
If the TBS turns positive during follow-up If a participant develops parasitemia they will be treated as soon as parasitemia is identified even if asymptomatic A blood sample adequate for genetic analysis required and culture optional will be obtained by venipuncture prior to treatment The drugs for treatment will be dihydroartemisinin-piperaquine DHAP or artemether-lumefantrine AL In addition any participant shown to have a breakthrough LARC2 parasite will be administered a single low dose of primaquine to kill any gametocytes and prevent transmission
Genetic analyses will be performed to determine whether the parasite is the vaccine strain or a wild type naturally acquired Pf strain If it is a wild type parasite the trial will continue without SMC consultation If the parasite is vaccine strain the Sponsor will be notified and the SMC consulted with regard to measures required to assure safety of the participants
Clearance of parasitemia prior to immunization Because the study is being done in malaria-exposed individuals some of whom may have chronic parasitemia it will be important to clear any existing parasitemia prior to immunization Otherwise these pre-existing parasitemias could recrudesce during follow-up confusing the ability to identify breakthroughs Clearance will be administered to all participants because it is not possible to determine which participants have latent infection even if the most sensitive PCR is used Clearance will be done using a full treatment course of atovaquone-proguanil AP with dosing adjusted for agebody weight and using directly observed treatment DOT This drug combination is selected based on the relatively short half-lives of the drugs compared to artemisinin combination therapies A short half-life is needed so that the drug does not interfere with the detection of any breakthrough parasitemias post immunization If possible the study will be performed in a location or during a period of the year when transmission levels are low However if naturally acquired parasitemia occurs during immunization and follow-up it will be possible to distinguish these parasites from the PfNF54 strain that comprises the vaccine by genetic analysis based on PCR as described
Clearance of parasitemia four weeks after immunization As a safety precaution all individuals will be treated again four weeks after immunization DHA-P or AL will be used as there is no concern about drug half-lives in this case
Long-term Follow-up Participants or their parents will be contacted at 3 months and 6 months to obtain follow-up recording any episodes of clinical malaria or unexplained SAEs Clinical malaria that is not identified by the study team and reported historically by parents guardians or participants will be defined as a positive diagnostic test TBS or rapid diagnostic test plus fever as defined previously plus symptoms consistent with malaria Any such individual will have a blood smear examined
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None