Safety, Tolerability, Pharmacokinetics and Protective Efficacy of MAM01 in Healthy Adults
- Conditions
- Malaria
- Interventions
- Biological: MAM01 900 mgBiological: MAM01 1.5 mg/kgBiological: MAM01 5 mg/kgBiological: MAM01 450 mgBiological: MAM01 600 mgOther: ControlBiological: PlaceboBiological: MAM01 10 mg/kgBiological: MAM01 40 mg/kg
- Registration Number
- NCT05891236
- Lead Sponsor
- Bill & Melinda Gates Medical Research Institute
- Brief Summary
This is a First-in-Human (FiH), randomized, two-part, dose-escalation trial of MAM01 monoclonal antibody (mAb) targeting the Plasmodium falciparum (Pf) Circumsporozoite Protein (CSP). This study will evaluate the safety, tolerability, pharmacokinetics (PK), and protective efficacy of MAM01, as well as safety and PK of repeat subcutaneous (SC) dosing. Part A will have a double-blind, placebo-controlled design. Part B will randomize participants to one of three open-label MAM01 dose groups; a separate non-randomized group will be enrolled to include participants who will receive no treatment and act as infectivity controls.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 61
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part B: Dose Expansion Cohort 6: Group 3: MAM01 MAM01 900 mg 8 participants will receive 900 mg SC dose of MAM01. The dose was selected by applying a PK-PD model from the Part A data to estimate a (data-driven) protection threshold at CHMI. Part A: Single Ascending Dose (SAD): Dose escalation cohort 1: MAM01 and placebo Intravenous (IV) MAM01 1.5 mg/kg 2 sentinel participants will be randomized in a 1:1 ratio to receive MAM01 1.5 milligrams per kilogram (mg/kg) IV or placebo. Following at least a 24-hour safety review period, the 6 remaining participants of Cohort 1 will be randomized in a 5:1 ratio to receive MAM01 1.5 mg/kg IV or placebo. Part A: Single Ascending Dose (SAD): Dose escalation cohort 1: MAM01 and placebo Intravenous (IV) Placebo 2 sentinel participants will be randomized in a 1:1 ratio to receive MAM01 1.5 milligrams per kilogram (mg/kg) IV or placebo. Following at least a 24-hour safety review period, the 6 remaining participants of Cohort 1 will be randomized in a 5:1 ratio to receive MAM01 1.5 mg/kg IV or placebo. Part A: SAD dosing: Dose escalation Cohort 2: MAM01 and placebo SC MAM01 5 mg/kg 7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg SC or placebo Part A: SAD dosing: Dose escalation Cohort 2: MAM01 and placebo SC Placebo 7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg SC or placebo Part A: SAD dosing: Dose escalation Cohort 3: MAM01 and placebo IV Placebo 7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg IV or placebo. Part A: SAD dosing: Dose escalation Cohort 3: MAM01 and placebo IV MAM01 5 mg/kg 7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg IV or placebo. Part A: SAD dosing: Dose escalation Cohort 4: MAM01 and placebo IV Placebo 8 participants will be randomly assigned in a 6:2 ratio to receive MAM01 10 mg/kg IV or placebo. Part A: SAD dosing: Dose escalation Cohort 4: MAM01 and placebo IV MAM01 10 mg/kg 8 participants will be randomly assigned in a 6:2 ratio to receive MAM01 10 mg/kg IV or placebo. Part A: SAD dosing: Dose escalation Cohort 5: MAM01 and placebo IV Placebo 7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 40 mg/kg IV or placebo Part A: SAD dosing: Dose escalation Cohort 5: MAM01 and placebo IV MAM01 40 mg/kg 7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 40 mg/kg IV or placebo Part A: Multiple Ascending Dose (MAD) (Repeat dosing): MAM01 MAM01 5 mg/kg Participants from Cohort 2 and from Cohort 3 will receive 5 mg/kg MAM01 SC. Part B: Dose Expansion Cohort 6: Group 1: MAM01 MAM01 450 mg 6 participants will receive a 450 mg SC dose of MAM01. The dose was selected by applying a PK-pharmacodynamic (PD) model from the Part A data to estimate a (data-driven) protection threshold at Controlled Human Malaria Infection (CHMI). Part B: Dose Expansion Cohort 6: Group 2: MAM01 MAM01 600 mg 8 participants will receive a 600 mg SC dose of MAM01. The dose was selected by applying a PK-PD model from the Part A data to estimate a (data-driven) protection threshold at CHMI Internal Infectivity Controls Control 6 participants will be enrolled into a non-randomized group prior to CHMI. These participants will receive no treatment and act as infectivity controls
- Primary Outcome Measures
Name Time Method Number of re-dosed participants reporting SUSARs, SAEs and AESIs Through 378 days Number of participants reporting solicited local and systemic adverse events (AEs) in the SC cohorts Through 7 days post-dose Local injection site solicited AEs will be assessed after dosing and will also be recorded for 7 days from SC recipients only. Systemic solicited AEs will be assessed in all participants after dosing at Visit 1 and recorded for 7 days.
Number of participants reporting unsolicited AEs (single dose or multiple dose) Through Day 28 Unsolicited adverse events will be captured after product administration and the CHMI procedure
Number of participants reporting serious adverse events (SAEs) including suspected unexpected serious adverse reactions (SUSARs) and adverse events special interest (AESIs) Through 168 days post-dose A SAE is defined as any untoward medical occurrence that, at any dose: Results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or is a medically significant / important event or reaction. SUSARs are adverse event that occur in a clinical trial participant, which is assessed by the Sponsor and or study investigator as being unexpected, serious and as having a reasonable possibility of a causal relationship with the study drug. AESIs are adverse events that the Sponsor wants to monitor carefully and which are subject to expedited reporting
Number of participants with safety laboratory assessments by grade (grade 1 and above) Up to 378 Days Blood samples will be collected for the analysis of laboratory parameters including hematology and serum chemistry.
- Secondary Outcome Measures
Name Time Method Part B: Cohort 6: Titers of Number of participants with ADAs following administration of MAM01 in Immunogenicity Population Up to Day 84 Maximal observed concentration (Cmax) following single and repeat dosing of MAM01 Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose Capillary blood samples via Volumetric Absorptive Microsampling Method (VAMS) or microtainers will be collected from participants in the Pharmacokinetic (PK) Population for measurement of MAM01 Cmax. Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Area under the curve (AUC) from Time=0 to the last measurable concentration (AUC0-t) of MAM01 Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 AUC 0-t. Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Partial AUC's Time= 0 to the CHMI challenge (AUC0-CHMI) of MAM01 Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 AUC0-CHMI. Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Concentration at the time of CHMI (CCHMI) following single and repeat dosing of MAM01 Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 CCHMI. Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Blood terminal elimination rate constant (λz) following single and repeat dosing of MAM01 Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 λz. Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Terminal half life (t1/2) of MAM01 Time Frame: Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 t1/2. Blood concentrations of MAM01 will be measured using a qualified immunoassay.
AUC from Time=0 extrapolated to infinity (AUC0-infinity) of MAM01 Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 AUC0-infinity. Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Percentage (%) AUC extrapolated (% AUCext) of MAM01 Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 (% AUCext. Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Bioavailability of SC formulation following single and repeat dosing of MAM01 Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140, 168, 224 and 280 post-dose Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 bioavailability. Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Part A: Cohorts 2 and 3: Accumulation ratio (AUC0-168) of MAM01 Pre-dose, Day 0: end of infusion (EOI), 1, 3 and 6 hours, Day 1: 24 hours, Day 2: 48 hours, Days 7, 14, 28, 42, 56, 70, 84, 98, 112, 140 and 168 post-dose Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 AUC0-168. Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Part A: Cohorts 2 and 3: AUC (210-378) of MAM01 Day 210 and up to Day 378 Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 AUC (210-378). Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Part A: Cohorts 2 and 3: Accumulation ratio AUC (210-378) of MAM01 Day 210 and up to Day 378 Capillary blood samples via VAMS or microtainers will be collected from participants in the PK Population for measurement of MAM01 Accumulation ratio AUC (210-378). Blood concentrations of MAM01 will be measured using a qualified immunoassay.
Number of participants with presence or absence of Pf infection assessed by quantitative polymerase chain reaction assay (qRT-PCR) after CHMI Through Day 27 post CHMI A sensitive qRT-PCR will be used for the detection of Pf parasites in Efficacy Population.
Time to parasitemia after CHMI in Efficacy Population Up to Day 378 Part A: Cohorts 1, 4 and 5: Titers of anti-drug antibodies (ADAs) following administration of MAM01 in Immunogenicity Population Up to Day 280 Percentage of participants with titers confirmed above the assay cut point will be summarized calculated by treatment group as appropriate.
Part A: Cohorts 2 and 3: Titers of ADAs following administration of MAM01 in Immunogenicity Population Up to Day 378
Trial Locations
- Locations (1)
Center for Vaccine Development and Global Health, 685 W. Baltimore Street
🇺🇸Baltimore, Maryland, United States