Malaria
Conditions
Keywords
Healthy volunteers, MAM01 monoclonal antibody, First-in-Human, Dose-escalation, Single ascending dose, Multiple ascending dose, Recruiting, Malaria vaccine, Mosquito, Gates, Prevention, Phase 1, Nonprofit
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.
Interventions
BIOLOGICALMAM01 1.5 mg/kg
1.5 mg/kg MAM01 will be administered via IV route.
BIOLOGICALPlacebo
Placebo will be administered via IV route.
BIOLOGICALMAM01 5 mg/kg
5 mg/kg MAM01 will be administered via SC route.
BIOLOGICALMAM01 10 mg/kg
10 mg/kg MAM01 will be administered via IV route.
BIOLOGICALMAM01 40 mg/kg
40 mg/kg MAM01 will be administered via IV route.
BIOLOGICALMAM01 450 mg
MAM01 will be administered via SC route.
OTHERControl
No drug or placebo will be administered.
BIOLOGICALMAM01 600 mg
MAM01 will be administered via SC route.
BIOLOGICALMAM01 900 mg
MAM01 will be administered via SC route.
Sponsors
Gates Medical Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Participants who are healthy as determined by medical evaluation including medical history, physical examination and laboratory tests * Body Mass Index (BMI) 18 to 30 kilograms per square meter (kg/m\^2) (inclusive) to a maximum of 220 pounds * Both males and females are eligible to participate as per the following: a. Female participants physically capable of pregnancy, have at least one negative pregnancy test during Screening, on the day of enrollment, prior to Investigational product (IP) administration, prior to CHM and at the start of antimalarial treatment, and who agree to use effective contraception to avoid pregnancy from 28 days before enrollment through 10 months after last administration of investigational product are eligible to participate. * Capable of giving signed Informed Consent which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and the trial protocol, and completion of a test of understanding if he/she may participate in the CHMI procedure * Reported completion of primary Coronavirus Disease (COVID) vaccine series is documented
Exclusion criteria
* Acute illness or fever ≥99.5°Fahrenheit (F) (or ≥37.5 degrees Celsius) on day of dosing * Women who are pregnant or breastfeeding * Evidence and/or history of clinically significant medical condition(s) as judged by the Investigator, including malignancies, diabetes mellitus, and unstable or uncontrolled hypertension * A 5-year cardiovascular risk of ≥10% using the Gaziano nomogram * History of any autoimmune disease or immune deficiency or other impairment to the immune system, including but not limited to Human immunodeficiency virus (HIV), autoimmune conditions or immunosuppressive therapy * Participation in an interventional clinical trial and/or receipt of any investigational drug within 180 days prior to administration of trial drug on Day 0 * Anticipated use of medications known to cause drug reactions with chloroquine or atovaquone-proguanil (Malarone) such as cimetidine, metoclopramide, antacids, and kaolin Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Solicited Adverse Events (AEs) in the Subcutaneous Cohorts | Day 1 to Day 7 post dose | Solicited AEs were defined events participants were specifically asked about, which were recorded by participants in the memory aid card. Solicited AES included local injection site AEs (pain, redness, swelling, itching and bruising) and systemic AEs (fever, chills, headache, fatigue, nausea, muscle pain and joint pain). A Solicited AE does not necessarily have a causal relationship with the intervention. |
| Number of Participants Reporting Unsolicited Adverse Events | Through Day 28 post dose | In this study an unsolicited AE is any AE not captured as a solicited AE in the Memory Aid Card between Day 0 and Day 7 after MAM01 dosing, and all AEs occurring after Day 7 post dose were collected as Unsolicited AEs. |
| Number of Participants Reporting Serious Adverse Events (SAEs) Including Suspected Unexpected Serious Adverse Reactions (SUSARs) and Adverse Events Special Interest (AESIs) | Up to Day 168 | 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 AEs reported for 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 closely and which require expedited reporting. |
| Number of Participants Who Received 2 Doses Reporting SUSARs, SAEs and AESIs | Through Day 336 | 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 AEs reported for 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 closely and which require expedited reporting. |
| Number of Participants With Clinically Significant Changes in Serum Chemistry Parameters | Through Day 336 | Blood samples were collected for the assessment of alanine transaminase, aspartate aminotransferase, alkaline phosphatase, total carbon-dioxide (CO2), chloride, total bilirubin, creatinine, blood urea nitrogen, glucose, albumin, total protein, sodium and potassium. |
| Number of Participants With Clinically Significant Changes in Hematology Parameters | Through Day 336 | Blood samples were collected for the assessment of complete blood count (CBC) including hemoglobin, platelet count, and white blood cell counts, and differential to include the absolute counts for neutrophils, lymphocytes, eosinophils, and monocytes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Observed Concentration (Cmax) Following Single Dose 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| Cmax Following 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| Area Under the Curve (AUC) From Time=0 to the Last Measurable Concentration (AUC0-t) Following Single Dose 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| AUC (0-t) Following 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| Concentration at the Time of CHMI (CCHMI) 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| Blood Terminal Elimination Rate Constant (λz) 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| Terminal Half Life (t1/2) Following Single Dose 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| t1/2 Following 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| Absolute Bioavailability of SC Formulation Following Repeated 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, 280 and 378 post-dose | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. |
| Accumulation Ratio (AUC0-168) Following Repeated Doses 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 | Serum from venous blood samples was collected for measurement of MAM01 pharmacokinetics. The accumulation ratio was calculated as the ratio of AUC (0-168) (post first dose) to AUC (210-378) (post redose). |
| Number of Participants With Confirmed Pf Infection Assessed by Quantitative Polymerase Chain Reaction Assay (qRT-PCR) After CHMI | Up to Day 27 post-CHMI | The characterization of protective efficacy against Pf following CHMI challenge, was assessed by evaluating the presence or absence of Pf infection as determined by qRT-PCR after CHMI (planned through 4 weeks post-CHMI) and evaluating the time to parasitemia after CHMI in each cohort. |
| Time to Parasitemia After CHMI | Up to Day 27 post-CHMI | Parasitemia was assessed by qRT-PCR up to Day 27 following CHMI. In addition, a thick blood smear was prepared for microscopic analysis, which was examined only once the first qRT-PCR sample tested positive. Daily parasitemia monitoring continued until the participant had a confirmed initial positive qRT-PCR. The first positive qRT-PCR triggered either a second PCR test or microscopic analysis of the blood smear. Once two positive results were obtained, rescue therapy was initiated. |
| Cohorts 1, 4 and 5: Numbers of Participants With Seroconversion | Up to Day 280 | The formation of ADAs (immunogenicity) following MAM01 SC and/or IV administration) was evaluated by measuring titers of ADA to MAM01 to last study visit for all participants. Capillary blood samples and selected serum samples were collected on volumetric absorptive micro-sampling (VAMS) devices at timepoints. |
| Cohorts 2 and 3: Numbers of Participants Receiving 2 Doses With Seroconversion | Up to Day 378 | The formation of ADAs (immunogenicity) following MAM01 SC and/or IV administration) was evaluated by measuring titers of ADA to MAM01 to last study visit for all participants. Capillary blood samples and selected serum samples were collected on volumetric absorptive micro-sampling (VAMS) devices at timepoints. |
| Cohort 6: Numbers of Participants With Seroconversion | Up to Day 84 | The formation of ADAs (immunogenicity) following MAM01 SC and/or IV administration) was evaluated by measuring titers of ADA to MAM01 to last study visit for all participants. Capillary blood samples and selected serum samples were collected on volumetric absorptive micro-sampling (VAMS) devices at timepoints. |
Countries
United States
Contacts
STUDY_DIRECTOR+1 866 789 5767
Gates Medical Research Institute
Participant flow
Recruitment details
A two-part randomized, dose-escalation study to assess anti-malarial human monoclonal antibody MAM01 in healthy, malaria-naïve adults. Part A: double-blind, placebo-controlled, single-ascending dose (SAD) study, while Part B: dose expansion was open-label. The study evaluated safety, tolerability, pharmacokinetics, and protective efficacy of MAM01 against controlled human malaria infection (CHMI) with Plasmodium falciparum NF54. Safety and PK of repeat subcutaneous dosing were also evaluated.
Pre-assignment details
In Part A, 37 of 38 participants were randomized to MAM01 or placebo, with 1 participant serving as an untreated infectivity control. Ten randomized participants did not undergo CHMI due to rescheduling secondary to a failure to generate infectious mosquitoes. In Part B, 25 participants were enrolled; 18 were dosed, 1 participant was randomized but withdrew prior to dosing, and 6 participants served as infectivity controls. One participant did not undergo CHMI due to concurrent illness.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 32.8 Years STANDARD_DEVIATION 8.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 34 Participants |
| Sex: Female, Male Female | 31 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 1 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 3 / 6 | 6 / 6 | 4 / 6 | 4 / 6 | 4 / 6 | 4 / 7 | 0 / 1 | 4 / 6 | 2 / 6 | 5 / 6 | 3 / 6 |
| serious Total, serious adverse events | 0 / 6 | 1 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 1 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
None listed