Phase II Randomized, Double-Blind Study of the Efficacy, Safety, Tolerability, and Pharmacokinetics of Intravenous Artesunate in Children With Severe Malaria
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 200
- 试验地点
- 3
- 主要终点
- The proportion of patients with parasite clearance (more than 99% reduction from the baseline asexual parasite count) at 24 hours after initiation of study drug.
研究概览
简要总结
The primary objective of the study is to evaluate the effectiveness of 2 intravenous artesunate dosing regimens (2.4 mg/kg initially and at 12, 24, 48, and 72 hours or 4.0 mg/kg initially and at 24 and 48 hours) in clearing P. falciparum parasites in children with severe malaria.
Secondary objectives include:
- To compare the tolerability and safety of the 2 intravenous artesunate dosing regimens.
- To evaluate differences in the pharmacokinetic profile of intravenous artesunate by patient age and clinical presentation.
详细描述
This is a Phase II, double-blind, multicenter, randomized, parallel-group study of the antimalarial activity and safety of 2 intravenous artesunate regimens in children with severe P. falciparum malaria (Appendix B). It will compare the efficacy, safety and tolerability of the SEAQUAMAT regimen, the recommended dosing regimen for adults,8 which requires twice daily artesunate dosing on the first day, to a simpler once daily regimen. The study will also evaluate the pharmacokinetic profile of artesunate in pediatric patients.
Prior to study initiation, the protocol will be approved by the Independent Ethics Committee/Institutional Review Board(s) (IEC/IRB) of each site and the national regulatory authority of each study site.
Approximately 200 patients will be randomized at 3 study sites in Africa, which are part of the Severe Malaria in African Children (SMAC) network. Patients will be randomized to 1 of 2 treatment cohorts:
- Cohort 1: artesunate 2.4 mg/kg initially, and at 12, 24, 48, and 72 hours (12 mg/kg total dose); or
- Cohort 2: artesunate 4 mg/kg initially, and at 24 and 48 hours (12 mg/kg total dose), normal saline will be administered as a placebo at 12 and 72 hours in order to maintain the study blind.
The study is divided into 3 main periods including the Pre-Treatment Period (Screening/Day 0), the Treatment Period (Days 0 through 3; Day 0 is the first day of study drug dosing), and the Post-Treatment Period (including evaluations on Days 7, 14, and 28). Children presenting to the study hospitals with signs/symptoms of severe malaria will be screened for study enrollment. Those with presumed severe malaria will be identified and informed consent for participation from parents/guardians will be obtained while confirmation of malaria is determined by microscopic analysis of a Giemsa-stained thick smear. Patients who meet study inclusion criteria and none of the exclusion criteria will be randomized and promptly treated with 1 of the artesunate regimens, while hospitalized for at least 4 days (Days 0, 1, 2, and 3). Adjunctive therapy, including fluids, glucose, and blood, will follow SMAC standards, based on WHO guidelines for the treatment of severe malaria (Appendix C). As soon as the patient is able to receive oral medication and no signs and symptoms of severe malaria are present, but not before the last pharmacokinetic sample is taken (approximately 50 hours after the start of therapy), a single dose of sulfadoxine/pyrimethamine will be administered to ensure parasitological cure. Patients who received sulfadoxine/pyrimethamine within 14 days prior Study Day 0 will receive mefloquine instead of SP,, to ensure effective parasitological cure.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 6 Months 至 10 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female children aged 6 months and ≥ 5kg to 10 years, inclusive.
- •Clinical diagnosis of severe P. falciparum malaria (see Appendix B) requiring hospitalization.
- •Parasitemia (more than 5,000 parasites/microL on initial blood smear).
- •Availability of child's parent/guardian and their willingness to provide written informed consent in accordance to local practice.
- •Willingness and ability to comply with the study protocol for the duration of the study.
- •Willingness to remain in the hospital for 4 days
排除标准
- •Known serious adverse reaction or hypersensitivity to artemisinins, including artesunate, artemether, dihydroartemisinins or Co-Artem (artemether/lumefantrine).
- •Any underlying disease that may compromise the diagnosis and the evaluation of the response to the study medication (including concomitant infection, concomitant neurological disease and malnutrition)
- •Participation in any investigational drug study during the 30 days prior to Screening.
- •Adequate anti-malarial treatment within 24 hours prior to admission.
研究组 & 干预措施
cohort 1
2.4 mg/kg iv artesunate at 0, 12, 24, 48and 72 hours
干预措施: Artesunate (Drug)
cohort 2
4.0 mg/kg iv Artesunate at 0, 24 and 48 h
干预措施: Artesunate (Drug)
结局指标
主要结局
The proportion of patients with parasite clearance (more than 99% reduction from the baseline asexual parasite count) at 24 hours after initiation of study drug.
时间窗: 24 hours after initiation of study
次要结局
- Time to total clearance of asexual parasites (PC100)(after study drug administration)
- Time to 99% reduction of asexual parasites (PC99)(after study drug administration)
- Time to 90% reduction of asexual parasites (PC90)(after study drug administration)
- PCR corrected Adequate Clinical and Parasitological Response on day 28(on day 28)
- plasma concentrations of artesunate following intravenous administration(after study drug administration)