Safety and Efficacy of L9LS, a Human Monoclonal Antibody Against Plasmodium Falciparum, in an Age De-Escalation, Dose-Escalation Trial and a Randomized, Placebo-Controlled, Double-Blind Trial of Children in Western Kenya
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 912
- 试验地点
- 1
- 主要终点
- Number of Participants With Local Adverse Events (AEs)
研究概览
简要总结
The purpose of this study is to evaluate the safety and tolerability of one-time subcutaneous (SC) administration of monoclonal antibody (MAb) L9LS in healthy Kenyan children aged 5 months to 10 years, as well as the protective efficacy of one or two doses of L9LS against naturally occurring Plasmodium falciparum (Pf) infection among Kenyan children aged 5 to 59 months at enrollment, in a setting of perennial high transmission.
详细描述
A two-part, phase 2 trial evaluating the safety and tolerability of one-time subcutaneous (SC) administration of monoclonal antibody (MAb) L9LS in healthy Kenyan children aged 5 months to 10 years, as well as the protective efficacy of one or two doses of L9LS against naturally occurring Plasmodium falciparum (Pf) infection among Kenyan children aged 5 to 59 months at enrollment, in a setting of perennial high transmission.
Part 1 includes part 1a and part 1b and is an age de-escalation and dose-escalation study. In part 1a, in a stepwise fashion, children aged 5-10 years will receive 5 mg/kg of L9LS or placebo and be followed for 3 months to assess tolerability and safety. If acceptable tolerability and safety profiles are met at 1-week post-injection, the 5 mg/kg dose of L9LS or placebo will be administered to children aged 5-59 months while enrolling another cohort of children aged 5-10 years at a dose of 10 mg/kg of L9LS or placebo. If after 1 week, the 10 mg/kg dose is found to be safe in children aged 5-10 years and the 5 mg/kg dose is found to be safe in children aged 5-59 months, a 20 mg/kg dose of L9LS or placebo will be administered to children aged 5-10 years and a 10 mg/kg dose of L9LS or placebo to children aged 5-59 months. Finally, if these doses are found safe after 1 week, a 20 mg/kg dose of L9LS or placebo will be administered to children aged 5-59 months. Should tolerability and safety of all doses be acceptable in children aged 5-59 months, part 2 of the trial will begin. Part 1b of the study was added later and will include two additional dose escalation cohorts of children aged 5 to 71 months and will test 30 mg/kg L9LS and 40 mg/kg L9LS. Dosing in part 1 of the study will be weight-based and all doses will be administered SC in a double-blinded fashion. 12 participants in each age-dose group will be enrolled in a 3:1 ratio of L9LS to placebo, and all participants will be followed for a total of 3 months.
Part 2 is the efficacy study. Children 5-59 months of age will be randomized to receive a 10-20 mg/kg dose of L9LS or placebo by SC administration. There will be two L9LS cohorts, one 5-17 months of age and another 18-59 months of age, which will constitute one L9LS arm. A placebo arm will be composed of children 5-59 months of age. They will be followed over 12 months with monthly blood smear microscopy and polymerase chain reaction (PCR) and twice-monthly symptomatology and careseeking behavior questionnaires. Dosing will be based on three weight bands; all doses will be administered SC with fixed doses of 75 mg L9LS, 150 mg L9LS, or 225 Mg L9LS, resulting in a range of 10-20 mg/kg in a double-blinded fashion. Blood will be drawn to assess antibody titers at baseline, and at three additional time points over 12 months to establish pharmacokinetics (PK). Participants in the L9LS arm will be randomized 1:1 at baseline to receive either a second L9LS injection or a placebo injection to evaluate the additional efficacy of a second dose administered 6 months after the first dose. (Those in the placebo arm will receive a second injection of placebo.) Participants will be followed for an additional 6 months after the second injection with monthly blood smear microscopy and PCR, and a blood draw at month 11 to assess L9LS PK.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 5 Months 至 10 Years（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Age de-escalation and dose-escalation study: Arm 1a: Age 5-10 years, 5 mg/kg of L9LS
Healthy children aged 5-10 years receive a single dose of 5 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 2.
干预措施: L9LS (Drug)
Age de-escalation and dose-escalation study: Arm 1b: Age 5-10 years, Placebo
Healthy children aged 5-10 years receive a single dose of placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 2.
干预措施: Placebo (Other)
Age de-escalation and dose-escalation study: Arm 2a: Age 5-59 months, 5 mg/kg of L9LS
Healthy children aged 5-59 months receive a single dose of 5 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 3.
干预措施: L9LS (Drug)
Age de-escalation and dose-escalation study: Arm 2b: Age 5-59 months, Placebo
Healthy children aged 5-59 months receive a single dose of placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 3.
干预措施: Placebo (Other)
Age de-escalation and dose-escalation study: Arm 2c: Age 5-10 years, 10 mg/kg of L9LS
Healthy children aged 5-10 years receive a single dose of 10 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 3.
干预措施: L9LS (Drug)
Age de-escalation and dose-escalation study: Arm 2d: Age 5-10 years, Placebo
Healthy children aged 5-10 years receive a single dose placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 3.
干预措施: Placebo (Other)
Age de-escalation and dose-escalation study: Arm 3a: Age 5-10 years, 20 mg/kg of L9LS
Healthy children aged 5-10 years receive a single dose of 20 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 4.
干预措施: L9LS (Drug)
Age de-escalation and dose-escalation study: Arm 3b: Age 5-10 years, Placebo
Healthy children aged 5-10 years receive a single dose of placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 4.
干预措施: Placebo (Other)
Age de-escalation and dose-escalation study: Arm 3c: Age 5-59 months, 10 mg/kg of L9LS
Healthy children aged 5-59 months receive a single dose of 10 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 4.
干预措施: L9LS (Drug)
Age de-escalation and dose-escalation study: Arm 3d: Age 5-59 months, Placebo
Healthy children aged 5-59 months receive a single dose of placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 4.
干预措施: Placebo (Other)
Age de-escalation and dose-escalation study: Arm 4a: Age 5-59 months, 20 mg/kg of L9LS
Healthy children aged 5-59 months receive a single dose of 20 mg/kg of L9LS one-time via subcutaneous administration.
干预措施: L9LS (Drug)
Age de-escalation and dose-escalation study: Arm 4b: Age 5-59 months, Placebo
Healthy children aged 5-59 months receive a single dose of placebo via subcutaneous administration.
干预措施: Placebo (Other)
Age de-escalation and dose-escalation study: Arm 5a: Age 5-71 months, 30 mg/kg of L9LS
Healthy children aged 5-71 months receive a single dose of 30 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 6.
干预措施: L9LS (Drug)
Age de-escalation and dose-escalation study: Arm 5b: Age 5-71 months, Placebo
Healthy children aged 5-71 months receive a single dose of placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 6.
干预措施: Placebo (Other)
Age de-escalation and dose-escalation study: Arm 6a: Age 5-71 months, 40 mg/kg of L9LS
Healthy children aged 5-71 months receive a single dose of 40 mg/kg L9LS via subcutaneous administration.
干预措施: L9LS (Drug)
Age de-escalation and dose-escalation study: Arm 6b: Age 5-71 months, Placebo
Healthy children aged 5-71 months receive a single dose of placebo via subcutaneous administration.
干预措施: Placebo (Other)
Efficacy Study: Arm 1a: Age 5-17 months, 10-20 mg/kg of L9LS/Placebo
Healthy children aged 5-17 months receive a single dose of 10-20 mg/kg L9LS via subcutaneous administration. Six months later, participants receive a single dose of placebo via subcutaneous administration.
干预措施: L9LS (Drug)
Efficacy Study: Arm 1a: Age 5-17 months, 10-20 mg/kg of L9LS/Placebo
Healthy children aged 5-17 months receive a single dose of 10-20 mg/kg L9LS via subcutaneous administration. Six months later, participants receive a single dose of placebo via subcutaneous administration.
干预措施: Placebo (Other)
Efficacy Study: Arm 1b: Age 5-17 months, 10-20 mg/kg of L9LS/10-20 mg/kg of L9LS
Healthy children aged 5-17 months receive a single dose of 10-20 mg/kg L9LS via subcutaneous administration. Six months later, participants receive a second single dose of 10-20 mg/kg L9LS via subcutaneous administration.
干预措施: L9LS (Drug)
Efficacy Study: Arm 1c: Age 5-17 months, Placebo/Placebo
Healthy children aged 5-17 months receive a single dose of placebo via subcutaneous administration. Six months later, participants receive a second single dose of placebo via subcutaneous administration.
干预措施: Placebo (Other)
Efficacy Study: Arm 2a: Age 18-59 months, 10-20 mg/kg of L9LS/Placebo
Healthy children aged 18-59 months receive a single dose of 10-20 mg/kg L9LS via subcutaneous administration. Six months later, participants receive a single dose of placebo via subcutaneous administration.
干预措施: L9LS (Drug)
Efficacy Study: Arm 2a: Age 18-59 months, 10-20 mg/kg of L9LS/Placebo
Healthy children aged 18-59 months receive a single dose of 10-20 mg/kg L9LS via subcutaneous administration. Six months later, participants receive a single dose of placebo via subcutaneous administration.
干预措施: Placebo (Other)
Efficacy Study: Arm 2b: Age 18-59 months, 10-20 mg/kg of L9LS/10-20 mg/kg of L9LS
Healthy children aged 18-59 months receive a single dose of 10-20 mg/kg L9LS via subcutaneous administration. Six months later, participants receive a second single dose of 10-20 mg/kg L9LS via subcutaneous administration.
干预措施: L9LS (Drug)
Efficacy Study: Arm 2c: Age 18-59 months, Placebo/Placebo
Healthy children aged 18-59 months receive a single dose of placebo via subcutaneous administration. Six months later, participants receive a second single dose of placebo via subcutaneous administration.
干预措施: Placebo (Other)
结局指标
主要结局
Number of Participants With Local Adverse Events (AEs)
时间窗: Age De-escalation and Dose escalation: within 7 days of administration of intervention; Efficacy study: within 7 days after first intervention, and 7 days after second intervention (second intervention occurred 6 months post first intervention)
Number of participants with at least one solicited local adverse events occurring within seven days of administration of intervention. Local reactogenicity included injection site pain, tenderness, bruising, swelling, redness, induration, pruritus, and other (e.g. injection site reaction). Adverse events were captured by Investigator examination and history from participants.
Number of Participants With Local Adverse Events (AEs) (by Grade)
时间窗: Age De-escalation and Dose escalation: within 7 days of administration of intervention; Efficacy study: within 7 days after first intervention, and 7 days after second intervention (second intervention occurred 6 months post first intervention)
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
Number of Participants With Systemic Adverse Events (AEs)
时间窗: Age De-escalation and Dose escalation: within 7 days of administration of intervention; Efficacy study: within 7 days after first intervention, and 7 days after second intervention (second intervention occurred 6 months post first intervention)
Number of participants with local adverse events occurring within seven days of administration of intervention. Systemic reactogenicity events included pyrexia (fever), malaise (feeling unusually tired or unwell), muscle aches, headache, chills, nausea, and joint pain. Adverse events were captured by Investigator examination and history from participants.
Number of Participants With Systemic Adverse Events (AEs) (by Grade)
时间窗: Age De-escalation and Dose escalation: within 7 days of administration of intervention; Efficacy study: within 7 days after first intervention, and 7 days after second intervention (second intervention occurred 6 months post first intervention)
The severity of systemic adverse events occurring after the administration of L9LS 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
未报告次要终点