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

• 批准号: 10208916
• 负责人: Amaya Lopez Bustinduy
• 金额: $ 47.3万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208916
• 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; 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

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.

项目摘要 本提案的总体目标是进行一次试验，以解决与我们的 了解治疗1-4岁肠道血吸虫病儿童的最佳方法。200多 全世界有100万人感染了三种主要的寄生虫之一，其中超过一半的人 感染发生在儿童身上。最近的研究强调了一个事实，即许多儿童首先经历的是 2岁之前感染，4岁以下儿童的感染率反映了 来自同一社区的大龄儿童的患病率。重要的是，吡喹酮（PZQ）， 在世界范围内用于治疗血吸虫病，只有FDA批准用于成人和儿童， 四口只有一项由共同PI Bustinduy领导的小型研究评估了药代动力学/药效学 (PK/PD）。这项在3-8岁儿童中进行的研究强烈表明， 40 mg/kg的剂量是不够的，治愈率低于60 mg/kg。 在地方性环境中，PZQ通常作为学校或社区预防的一部分进行管理 化疗运动。目前，在28个血吸虫病流行的非洲国家中， 菲律宾将四岁以下儿童纳入控制方案。造成这种情况的原因是多方面的 包括a）缺乏该年龄组的足够PK/PD数据，3岁以下儿童无PK/PD数据，B）缺乏 60 mg/kg剂量下的安全性数据，c）缺乏处理对关键生长影响的数据， 这一弱势年龄组的营养结果阻碍了治疗的优先顺序，d）无PK/PD研究 在儿科S. e）FDA标签不包括幼儿。 本提案的目标是在美国进行一项随机、对照的II期试验。 mansoni流行区的乌干达和S.菲律宾的日本血吸虫流行区，N=600 这将解决目前阻碍幼儿治疗的许多差距。 特别是在SA 1中，我们将1）评估4岁以下儿童中PZQ给药的PK/PD，剂量为40 与60 mg/kg相比，2）扩展PD终点，以包括最新技术水平的抗原检测和发病率结局，3） 评估两种PZQ对映体的PK/PD，以及4）解决环境 肠病（EE）导致PZQ PK/PD中观察到的显著个体间变异性。在SA 2中，我们 将1）评估PZQ以60 mg/kg给药在两个大型极年幼儿童队列中的安全性，2） 评估两种不同治疗间隔（6个月vs 12个月）对营养状况、生长和 贫血风险，3）解决有关血吸虫病的机制的创新假设， 导致该年龄组的发病率，包括EE和肠道微生物易位， 全身免疫激活。