A Phase 1, Dose Escalation, Double Blind, Placebo Controlled Clinical Trial With Controlled Human Malaria Infections (CHMI) to Evaluate Safety, Tolerability, Pharmacokinetics, and Protective Efficacy of an Anti-Malaria Human Monoclonal Antibody, MAM01, in Healthy, Malaria-Naive Adults
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 63
- 试验地点
- 2
- 主要终点
- Number of re-dosed participants reporting SUSARs, SAEs and AESIs
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- Double (Participant, Care Provider)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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/Exclusion criteria may apply.
研究组 & 干预措施
Part B: Dose Expansion Cohort 6: Group 3: MAM01
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.
干预措施: MAM01 900 mg (Biological)
Internal Infectivity Controls
6 participants will be enrolled into a non-randomized group prior to CHMI. These participants will receive no treatment and act as infectivity controls
干预措施: Control (Other)
Part A: Single Ascending Dose (SAD): Dose escalation cohort 1: MAM01 and placebo Intravenous (IV)
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.
干预措施: MAM01 1.5 mg/kg (Biological)
Part A: Single Ascending Dose (SAD): Dose escalation cohort 1: MAM01 and placebo Intravenous (IV)
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.
干预措施: Placebo (Biological)
Part A: SAD dosing: Dose escalation Cohort 2: MAM01 and placebo SC
7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg SC or placebo
干预措施: MAM01 5 mg/kg (Biological)
Part A: SAD dosing: Dose escalation Cohort 2: MAM01 and placebo SC
7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg SC or placebo
干预措施: Placebo (Biological)
Part A: SAD dosing: Dose escalation Cohort 3: MAM01 and placebo IV
7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg IV or placebo.
干预措施: Placebo (Biological)
Part A: SAD dosing: Dose escalation Cohort 3: MAM01 and placebo IV
7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 5 mg/kg IV or placebo.
干预措施: MAM01 5 mg/kg (Biological)
Part A: SAD dosing: Dose escalation Cohort 4: MAM01 and placebo IV
8 participants will be randomly assigned in a 6:2 ratio to receive MAM01 10 mg/kg IV or placebo.
干预措施: Placebo (Biological)
Part A: SAD dosing: Dose escalation Cohort 4: MAM01 and placebo IV
8 participants will be randomly assigned in a 6:2 ratio to receive MAM01 10 mg/kg IV or placebo.
干预措施: MAM01 10 mg/kg (Biological)
Part A: SAD dosing: Dose escalation Cohort 5: MAM01 and placebo IV
7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 40 mg/kg IV or placebo
干预措施: Placebo (Biological)
Part A: SAD dosing: Dose escalation Cohort 5: MAM01 and placebo IV
7 participants will be randomly assigned in a 6:1 ratio to receive MAM01 40 mg/kg IV or placebo
干预措施: MAM01 40 mg/kg (Biological)
Part A: Multiple Ascending Dose (MAD) (Repeat dosing): MAM01
Participants from Cohort 2 and from Cohort 3 will receive 5 mg/kg MAM01 SC.
干预措施: MAM01 5 mg/kg (Biological)
Part B: Dose Expansion Cohort 6: Group 1: MAM01
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).
干预措施: MAM01 450 mg (Biological)
Part B: Dose Expansion Cohort 6: Group 2: MAM01
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
干预措施: MAM01 600 mg (Biological)
结局指标
主要结局
Number of re-dosed participants reporting SUSARs, SAEs and AESIs
时间窗: Through 378 days
Number of participants reporting solicited local and systemic adverse events (AEs) in the SC cohorts
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: Up to 378 Days
Blood samples will be collected for the analysis of laboratory parameters including hematology and serum chemistry.
次要结局
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Part A: Cohorts 2 and 3: AUC (210-378) of MAM01(Day 210 and up to Day 378)
- Part A: Cohorts 2 and 3: Accumulation ratio AUC (210-378) of MAM01(Day 210 and up to Day 378)
- 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)
- 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)
- Part A: Cohorts 2 and 3: Titers of ADAs following administration of MAM01 in Immunogenicity Population(Up to Day 378)
- Part B: Cohort 6: Titers of Number of participants with ADAs following administration of MAM01 in Immunogenicity Population(Up to Day 84)