A Phase 1b, Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Safety, Tolerability, and Pharmacokinetics of L9LS in Infants in Mali and to Evaluate the Impact of L9LS on Subsequent R21/Matrix-MTM Vaccine Immunogenicity
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 327
- 试验地点
- 3
- 主要终点
- Measurement of study agent in sera of recipients.
研究概览
简要总结
The purpose of this study is to assess the safety, tolerability, and pharmacokinetics of L9LS in infants in Mali and to evaluate the impact of L9LS on subsequent R21/Matrix-MTM vaccine immunogenicity.
详细描述
This is an age-stratified, randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability, and pharmacokinetics (PK) of one-time intramuscular (IM) administration of the monoclonal antibody (MAb) L9LS to healthy Malian infants aged 1 to 12 months, followed by an assessment of the impact of L9LS on the immunogenicity of subsequent administration of the R21/Matrix-MTM vaccine. The study hypotheses are that L9LS will be safe and will not impact the immunogenicity of the R21/Matrix-MTM vaccine. During the beginning of the 6-month malaria season (approximately August and September at the study site), 180 participants will be enrolled and randomized 1:1 to receive 150 mg of L9LS (n=90) or normal saline placebo (n=90). Randomization of participants in each arm will be age-stratified (1 to 4 months, n=60; >4 to 8 months, n=60; >8 to 12 months, n=60). The safety of L9LS will be assessed within each of the three (3) age strata. Participants will be followed at study visits 1, 3, 7, 14, 21, and 28 days later, and once every 4 weeks thereafter through study day 280 (40 weeks). Approximately 5 months after receiving L9LS or placebo, all participants will receive the R21/Matrix-MTM vaccine as 3 total doses given 4 weeks apart as per World Health Organization (WHO) recommendations and the anticipated Malian vaccination guidelines.
Primary study assessments include medical history, physical examination, and blood collection to assess antibody responses to the R21/Matrix-MTM vaccine, L9LS PK, anti-drug antibody (ADA) assessments, identification of Plasmodium falciparum (Pf) infection by microscopic examination of thick blood smears and reverse transcription polymerase chain reaction (RT-PCR), and other research laboratory evaluations. Through their local provider, all participants 3 months and older will be offered 4 rounds of seasonal malaria chemoprevention (SMC) as a monthly 3-day treatment course of sulfadoxine-Pyrimethamine plus amodiaquine (SPAQ), as it is the standard of care in Mali for malaria prevention in children 3 months to 5 years of age.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blind
入排标准
- 年龄范围
- 1 Month 至 12 Months（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age ≥1 to ≤12 months at enrollment.
- •Born at ≥37 weeks gestation.
- •Parent and/or guardian able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
- •In good general health and without clinically significant medical history.
- •Parent and/or guardian able to provide informed consent.
- •Willing to have blood samples and data stored for future research.
- •Resides in or near Kalifabougou, Faladje, or Torodo, Mali, and available for the duration of the study.
排除标准
- •Body weight <3.5 kg.
- •Behavioral, cognitive, or psychiatric disease in the parent and/or guardian that in the opinion of the investigator affects the ability of the parent and/or guardian to understand and comply with the study protocol.
- •Any fever (≥ 37.5°C, regardless of route) or acute illness within 7 days prior to randomization.
- •Clinically significant congenital anomaly or documented or suspected serious medical illness (e.g., history of epilepsy), serious congenital anomaly, or immediate life-threatening condition in the infant that may interfere with the ability to complete study requirements, as judged by the examining clinician.
- •Prior history of a suspected or actual acute life-threatening event.
- •Receipt of any blood products, monoclonal or polyclonal antibody/immunoglobulin (for example, hepatitis B immune globulin, intravenous immunoglobulin) or anticipated use during the study.
- •Any acute or chronic illnesses known in the mother during her pregnancy.
- •Parental study comprehension examination score of <80% correct or per investigator discretion.
- •Hemoglobin, white blood cell (WBC), absolute neutrophil, or platelet count outside the local laboratory-defined limits of normal. (Participants may be included at the investigator's discretion for "not clinically significant" values.)
- •Alanine aminotransferase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of normal. (Participants may be included at the investigator's discretion for "not clinically significant" values.)
- •Mother and/or infant infected with HIV.
- •Sickle cell disease by testing. (Note: Known sickle cell trait is NOT exclusionary.)
- •Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies.
- •Receipt of any investigational product within the past 30 days.
- •Participation or planned participation in an interventional trial with an investigational product until the last required protocol visit. (Note: Past, current, or planned participation in observational studies is NOT exclusionary.)
- •History of a severe allergic reaction or anaphylaxis.
- •Salivary gland disorder diagnosed by a doctor (e.g., parotitis, sialadenitis, sialolithiasis, salivary gland tumors).
- •Pre-existing autoimmune or antibody-mediated diseases including but not limited to systemic lupus erythematosus or autoimmune thrombocytopenia.
- •Known immunodeficiency syndrome.
- •Known asplenia or functional asplenia.
- •Use of chronic (≥14 days) oral or IV corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive drugs within 30 days of day
- •Previous receipt of the R21/Matrix-MTM vaccine.
- •Previous receipt of an investigational malaria vaccine or monoclonal antibody.
- •Clinical signs of malnutrition.
- •Other condition(s) that, in the opinion of the investigator, would jeopardize the safety or rights of an individual participating in the trial, interfere with the evaluation of the study objectives, or render the participant unable to comply with the protocol.
研究组 & 干预措施
Infants 9-12 months: L9LS 150 mg
Infants age 9-12 months received a single dose of L9LS 150 mg intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: L9LS (Biological)
Infants 5-8 months: L9LS 150 mg
Infants age 5-8 months received a single dose of L9LS 150 mg intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: L9LS (Biological)
Infants 1-4 months: L9LS 150 mg
Infants age 1-4 months received a single dose of L9LS 150 mg intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: L9LS (Biological)
Infants 1-4 months: L9LS 150 mg
Infants age 1-4 months received a single dose of L9LS 150 mg intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: R21/Matrix-MTM (Biological)
Infants 5-8 months: L9LS 150 mg
Infants age 5-8 months received a single dose of L9LS 150 mg intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: R21/Matrix-MTM (Biological)
Infants 9-12 months: L9LS 150 mg
Infants age 9-12 months received a single dose of L9LS 150 mg intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: R21/Matrix-MTM (Biological)
Infants 1-4 months: Placebo
Infants age 1-4 months received a single dose of normal saline placebo intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: Placebo (Other)
Infants 1-4 months: Placebo
Infants age 1-4 months received a single dose of normal saline placebo intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: R21/Matrix-MTM (Biological)
Infants 5-8 months: Placebo
Infants age 5-8 months received a single dose of normal saline placebo intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: Placebo (Other)
Infants 5-8 months: Placebo
Infants age 5-8 months received a single dose of normal saline placebo intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: R21/Matrix-MTM (Biological)
Infants 9-12 months: Placebo
Infants age 9-12 months received a single dose of normal saline placebo intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: Placebo (Other)
Infants 9-12 months: Placebo
Infants age 9-12 months received a single dose of normal saline placebo intramuscularly. Approximately five months after receiving intervention, participants received the R21/Matrix-MTM vaccine 0.5ml (dose has 5mcg of malaria /50mcg of the adjuvant) intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
干预措施: R21/Matrix-MTM (Biological)
结局指标
主要结局
Measurement of study agent in sera of recipients.
时间窗: Measured day 7, 28, 84, 140, 196 and 280
Incidence of local and systemic AEs occurring within 7 days after the administration of study agent.
时间窗: Measured through Day 7
Severity of local and systemic AEs occurring within 7 days after the administration of study agent.
时间窗: Measured through Day 7
Participants With Local Adverse Events (AEs)
时间窗: Within 7 days after administration of L9LS or matching Placebo intervention (administered on Day 0)
Number of participants with local adverse events occurring within 7 days after administration of L9LS or placebo intervention. Local reactogenicity included pain/tenderness, swelling, redness, bruising, and pruritus at the site of infusion. Adverse events were captured by Investigator examination and history from participants.
Severity of Local Adverse Events (AEs)
时间窗: Within 7 days after administration of L9LS or matching Placebo intervention (administered on Day 0)
The severity of local AEs was graded using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Clinical Trials. Grade 1: Pain = does not interfere with activity; Tenderness = mild discomfort to touch; Erythema/Redness = 2.5-5 cm; Induration/Swelling = 2.5-5 cm and does not interfere with activity Grade 2: Pain = Repeated use of non-narcotic pain reliever \> 24 hours or interferes with daily activity; Tenderness=Discomfort with movement; Erythema/Redness = 5.1-10 cm; Induration/Swelling = 5.1-10 cm and interferes with activity Grade 3: Pain = Any use of narcotic pain reliever or prevents daily activity; Tenderness = Significant discomfort at rest; Erythema/Redness = \> 10 cm; Induration/Swelling = \> 10 cm or prevents daily activity Grade 4: Pain = Emergency room (ER) visit or hospitalization; Tenderness = ER visit or hospitalization; Erythema/Redness = Necrosis or exfoliative dermatitis; induration/Swelling = Necrosis Grade 5: Death
Participants With Systemic Adverse Events (AEs)
时间窗: Within 7 days after administration of L9LS or matching Placebo intervention (administered on Day 0)
Number of participants with local adverse events occurring within 7 days after administration of L9LS or placebo intervention. Systemic reactogenicity events included fever, feeling unusually tired or unwell, muscle aches, headache, chills, nausea, and joint pain. Adverse events were captured by Investigator examination and history from participants.
Severity of Systemic Adverse Events (AEs)
时间窗: Within 7 days after administration of L9LS or matching Placebo intervention (administered on Day 0)
The severity of systemic AEs after the administration of L9LS or placebo was assessed using the grading scale below: Grade 1: Fever = 37.5\^oC-37.9\^oC; Fatigue, Headache, Myalgia = No interference with activity; Nausea = no interference with activity or 1-2 episodes/hour Grade 2: Fever = 38\^oC-38.4\^oC; Fatigue, Myalgia = Some interference with activity; Headache = Repeated use of non-narcotic pain reliever \> 24 hours or some interference with activity; Nausea = Some interference with activity or \> 2 episodes/24 hours Grade 3: Fever = 38.5\^oC-39.5\^oC; Fatigue = Prevents daily activity; Headache =Significant; any use of narcotic pain reliever or prevents daily activity; Myalgia =Significant; prevents daily activity; Nausea = Prevents daily activity, requires outpatient intravenous hydration Grade 4: Fever = \> 39.5\^oC; Fatigue, Headache, Myalgia = Emergency room (ER) visit or hospitalization; Nausea = ER visit or hospitalization for hypotensive shock Grade 5: Death
次要结局
- Total IgG anti-NANP antibody titers measured by ELISA.(Measured 28 days and 84 days after the third R21/Matrix-MTM vaccination.)
- Measurement of Anti-Drug Antibodies (ADA) to L9LS in sera of recipients.(Measured at day 28, 224 and 280)
- Participants With Adverse Events of Special Interest (AESIs) Related to R21/Matrix-MTM Vaccine(Within 7 days after administration of each dose of the R21/Matrix-MTM vaccine (administered on days 140, 168, 196))
- Severity of Adverse Events of Special Interest (AESIs)(Within 7 days after administration of each dose of the R21/Matrix-MTM vaccine (administered on days 140, 168, 196))
- Antibody Response to R21/Matrix-MTM Vaccine(Measured 28 days (Day 224) and 84 days (Day 280) after the third dose of R21/Matrix-MTM vaccination)
- Maximum Total Plasma Concentration (Cmax) for L9LS(Days 0 to 280)
- Time to Maximum Plasma Concentration (TMax) for L9LS(Days 0 to 280)
- Area Under the Curve (AUC) for L9LS From Day 0 to 168 (AUC_168)(Days 0 to 280)
- Area Under the Curve (AUC) From Day 0 to Last Observed for L9LS(Days 0 to 280)
- Area Under the Concentration Time Curve (AUC) From Day 0 to Infinity(Days 0 to 280)
- Terminal Half-life (t½) of L9LS(Days 0 to 280)