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Phase II PK/PD driven dose finding trial of Praziquantel in children under four

四岁以下儿童吡喹酮 II 期 PK/PD 驱动剂量探索试验

基本信息

批准号：
10438834
负责人：
Amaya Lopez Bustinduy
金额：
$ 45.87万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438834
关键词：
Address Adult African Age Anemia Anodes Antibodies Antigens Area Under Curve Biological Markers Cathodes Child Childhood Communities Cross-Over Trials Data Dose Drug Exposure Drug Kinetics Drug usage Endotoxins Exclusion Exposure to FDA approved Formulation Frequencies Funding Gender Goals Growth Health Services Height Hemoglobin High Prevalence Individual Infection Inflammatory Intestines Iron Label Lactulose Leukocyte L1 Antigen Complex Link Malnutrition Mannitol Measures Mediating Modeling Morbidity - disease rate Nursery Schools Nutritional Nutritional status Outcome Pathogenesis Pathway interactions Pharmacodynamics Phase Philippines Placebo Control Placebos Praziquantel Prevalence Preventive Randomized Randomized Controlled Trials Recommendation Regimen Reporting Residual state Risk Role Safety Schistosoma Schistosoma japonicum Schistosoma mansoni Schistosomiasis Schools Serum Single-Blind Study Site Techniques Time Uganda Urine Vulnerable Populations Weight age group antigen test arm base burden of illness chemotherapy cohort cytokine drug efficacy egg enantiomer experience immune activation indexing innovation inter-individual variation microbial neurodevelopment off-label use phase II trial programs treatment effect treatment program trial design

项目摘要

Project Summary The overall goals of this proposal are to conduct a trial to address the significant gaps with respect to our understanding of best approaches to treatment of children ages 1-4 with intestinal schistosomiasis. Over 200 million individuals worldwide are infected with one of three predominant species of schistosomes, with over half of infections occurring in children. Recent studies have highlighted the fact that many children experience first infections before the age of two, with the prevalence of infection among children under four mirroring the prevalence of older children from the same community. Importantly, praziquantel (PZQ), the drug used worldwide for the treatment of schistosomiasis, is only FDA approved among adults and children over the age of four. Only one small study led by co-PI Bustinduy has evaluated the pharmacokinetic/pharmacodynamics (PK/PD) of PZQ in children. That study, conducted among children ages 3-8, strongly suggests that the current dose of 40 mg/kg is insufficient, with lower cure rates than found at 60 mg/kg. In endemic settings, PZQ is most often administered as part of school based, or community wide preventive chemotherapy campaigns. Currently, none of the 28 schistosomiasis endemic African nations or The Philippines includes children under the age of four in control programs. The reasons for this are multifactorial and include a) lack of sufficient PK/PD data in this age group, with none in children under three, b) lack of safety data at a dose of 60 mg/kg, c) lack of data addressing the impact of treatment on key growth and nutritional outcomes in this vulnerable age group hampering prioritization of treatment, d) no PK/PD studies conducted in the context of pediatric S. japonicum and e) FDA labeling that does not include young children. The goals of this proposal are to conduct a randomized, controlled Phase II trial to be conducted in an S. mansoni endemic region of Uganda and an S. japonicum endemic region of The Philippines with N=600 children ages 1-4, that will address many of the current gaps that are hindering treatment of young children. Specifically in SA1 we will 1) assess PK/PD of PZQ dosing among children under the age of 4 at doses of 40 versus 60 mg/kg, 2) expand PD endpoints to include state of the art antigen tests and morbidity outcomes, 3) assess the PK/PD of both PZQ enantiomers, and 4) address the innovative hypothesis that environmental enteropathy (EE) contributes to the significant inter-individual variability observed in PZQ PK/PD. In SA2, we will 1) assess the safety of PZQ administered at 60 mg/kg in two large cohorts of very young children, 2) assess the impact of two different treatment intervals (6 vs 12 months) on nutritional status, growth, and anemia risk, and 3) address innovative hypotheses regarding mechanisms through which schistosomiasis contributes to morbidity in this age group including EE and gut microbial translocation with consequent systemic immune activation.

项目概要该提案的总体目标是进行一项试验，以解决我们在了解治疗 1-4 岁肠道血吸虫病儿童的最佳方法。超过200 全世界有数百万人感染三种主要血吸虫种类之一，其中一半以上儿童发生的感染。最近的研究强调了这样一个事实：许多孩子首先经历的是两岁之前的感染率，四岁以下儿童的感染率反映了来自同一社区的年龄较大儿童的患病率。重要的是，所用药物吡喹酮（PZQ）在全球范围内用于治疗血吸虫病，是 FDA 唯一批准用于成人和 1 岁以上儿童的药物四个。只有一项由联合 PI Bustinduy 领导的小型研究评估了药代动力学/药效学 PZQ 在儿童中的 (PK/PD)。这项针对 3 至 8 岁儿童进行的研究强烈表明，当前 40 mg/kg 的剂量是不够的，治愈率低于 60 mg/kg 的治愈率。在流行情况下，PZQ 最常作为学校或社区范围预防措施的一部分进行管理化疗活动。目前，28个非洲血吸虫病流行国家或地区均未发现血吸虫病。菲律宾将四岁以下的儿童纳入控制计划。造成这种情况的原因是多方面的并包括 a) 在该年龄组中缺乏足够的 PK/PD 数据，三岁以下儿童中没有，b) 缺乏剂量为 60 mg/kg 的安全性数据，c) 缺乏说明治疗对关键生长影响的数据和该弱势年龄组的营养结果阻碍了治疗的优先顺序，d) 没有 PK/PD 研究 e) FDA 标签不包括幼儿。该提案的目标是在 S. 进行一项随机、对照的 II 期试验。乌干达曼氏菌流行区和菲律宾日本血吸虫流行区，N=600 1-4 岁的儿童，这将解决目前阻碍幼儿治疗的许多差距。具体来说，在 SA1 中，我们将 1) 评估 4 岁以下儿童中 PZQ 剂量 40 的 PK/PD 与 60 mg/kg 相比，2) 扩大 PD 终点，包括最先进的抗原测试和发病结果，3) 评估两种 PZQ 对映体的 PK/PD，以及 4) 解决环境影响这一创新假设肠病 (EE) 导致 PZQ PK/PD 中观察到的显着个体间变异。在SA2中，我们将 1) 评估在两组幼儿中以 60 mg/kg 剂量服用 PZQ 的安全性，2) 评估两种不同治疗间隔（6 个月与 12 个月）对营养状况、生长和发育的影响贫血风险，以及 3) 提出关于血吸虫病发生机制的创新假设导致该年龄段的发病率，包括 EE 和肠道微生物易位，从而导致全身免疫激活。