Aggressive Antipyretics in CNS Malaria: A Randomized-Controlled Trial Assessing Antipyretic Efficacy and Parasite Clearance

中枢神经系统疟疾中的强力退热药：评估退热功效和寄生虫清除的随机对照试验

• 批准号: 9923006
• 负责人: GRETCHEN L. BIRBECK
• 金额: $ 63.88万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923006
• 关键词: Acetaminophen; Acute; Adverse event; Affect; Africa; Area Under Curve; Behavior; Blood; Blood Coagulation Disorders; Blood flow; Brain; Brain Injuries; Central Nervous System Diseases; Cerebral Malaria; Cerebrovascular Circulation; Child; Child Care; Childhood; Clinical Trials; Collaborations; Coma; Complex; Computers; Conduct Clinical Trials; Congestive; Conscious; Data; Endothelial Cells; Enrollment; Ensure; Erythrocytes; Febrile Convulsions; Fever; Free Radicals; Functional disorder; Funding; Hepatic; High temperature of physical object; Hour; Hyperthermia; Hypoglycemia; Ibuprofen; Immune system; Impairment; In Vitro; Incidence; Individual; Inflammation; Infrastructure; Kidney Failure; Malaria; Malawi; Measures; Mediating; Microcirculation; Monitor; Nature; Nervous System Trauma; Neuraxis; Neurologic; Organ; Parasitemia; Parasites; Participant; Pathogenesis; Peripheral; Pharmaceutical Preparations; Phase III Clinical Trials; Plasmodium falciparum; Process; Production; Prospective Studies; Proteins; Public Health; Randomized; Randomized Controlled Trials; Research; Risk; Risk Factors; Safety; Secondary to; Seizures; Subgroup; Survivors; Temperature; Time; United States National Institutes of Health; Vision; Zambia; acute infection; antipyretic; base; disability; double-blind placebo controlled trial; effective intervention; excitotoxicity; experience; histidine-rich proteins; in vivo; induced hypothermia; insight; mortality; neuroprotection; phase 3 study; prophylactic; recruit; scale up; secondary analysis; treatment as usual; treatment duration; treatment effect; treatment group

Despite ongoing eradication efforts, malaria remains a major public health challenge in Africa where annually, ~250,000 children with malaria experience a neurologic injury with subsequent neurodisability. In other central nervous system (CNS) disorders, fever is a recognized cause of worsening secondary neurologic injury and ex- tensive efforts are made to avoid hyperthermia or induce hypothermia for neuroprotection. Evidence indicates that among children with CNS malaria a higher temperature during the acute illness is a risk factor for post-in- fectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted, at least among chil- dren with complicated malaria who are at substantial risk of brain injury. Previous clinical trials conducted pri- marily in children with uncomplicated malaria and using only a single antipyretic medication have shown limited benefits in terms of fever reduction; however, no studies to date have examined malaria fever management us- ing dual therapies. Enthusiasm for aggressive fever reduction measures among clinicians caring for children with malaria has been curbed by in vitro findings that malaria parasite replication slows at higher temperatures and a single clinical trial in which peripheral parasite clearance was slower in children receiving treatment for fe- ver. However, the relationship between temperature and malaria parasite behavior is complex. Additional in vitro data suggest that at febrile temperatures uninfected red blood cells (RBCs) are more likely to adhere to infected RBCs, worsening the process of sequestration, increasing the parasite burden obstructing microvascular cere- bral blood flow, and perhaps contributing to ongoing immuno-pathogenesis in CNS malaria. In this exploratory clinical trial of aggressive antipyretic therapy, children hospitalized with CNS malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature ≥ 38.5ºC) vs. prophylactic acetaminophen and ibuprofen every 6 hours for 72 hours. This proof-of-concept study will determine whether aggressive antipyretic therapy results in a lower mean maximum temperature relative to usual care. Serial quantitative levels of HRP2, a P. fal- ciparum-specific protein that facilitates estimates of whole body parasite burden and CNS parasite sequestra- tion, will also be collected to clarify the relationship between antipyretic use and in vivo parasite behavior. Find- ings from this study will determine whether a Phase III clinical trial of aggressive antipyretics for neuroprotection in pediatric CNS malaria should be undertaken. This study will take place in Zambia and Malawi, where prior NIH-funded collaborations have assisted in developing the substantial infrastructure needed to undertake a clini- cal trial of this nature.

尽管根除工作不断进行，疟疾仍然是非洲的一个重大公共卫生挑战，每年， 约 250,000 名疟疾儿童经历了神经损伤，并随后导致其他中枢神经功能障碍。 神经系统（CNS）疾病，发烧是继发性神经损伤恶化的公认原因 有证据表明，为了神经保护，人们正在努力避免体温过高或诱导体温过低。 在患有中枢神经系统疟疾的儿童中，急性疾病期间的较高体温是术后感染的危险因素。 因此，至少在儿童中，可能需要积极的退热治疗。 先前进行的临床试验是患有复杂性疟疾且有很大脑损伤风险的人。 尤其是对于患有无并发症的疟疾且仅使用单一退热药物的儿童来说，效果有限 减少发烧方面的益处；然而，迄今为止还没有研究考察过疟疾发烧管理的用途。 照顾儿童的护士热衷于采取积极的退烧措施。 体外研究结果表明，疟疾寄生虫在较高温度下复制会减慢，从而抑制了疟疾 以及一项单一的临床试验，其中接受铁蛋白治疗的儿童外周寄生虫清除速度较慢 然而，温度和疟原虫行为之间的关系很复杂。 数据表明，在发烧温度下，未感染的红细胞 (RBC) 更有可能粘附在受感染的细胞上。 红细胞，使隔离过程恶化，增加阻塞微血管脑的寄生虫负担 脑血流，可能有助于中枢神经系统疟疾的持续免疫发病机制。 积极退热治疗的临床试验，因中枢神经系统疟疾住院的儿童将被随机分配到正常情况 护理（对乙酰氨基酚每 6 小时一次，体温≥ 38.5°C）与预防性对乙酰氨基酚和布洛芬的比较 这项概念验证研究将确定是否需要积极退烧治疗，持续 72 小时。 与常规护理相比，P. fal- 的 HRP2 的连续定量水平较低。 ciparum 特异性蛋白质，有助于估计全身寄生虫负荷和中枢神经系统寄生虫隔离 还将收集这些数据，以阐明退热药的使用与体内寄生虫行为之间的关系。 这项研究的结果将决定是否进行积极退烧药用于神经保护的 III 期临床试验 这项研究将在赞比亚和马拉维进行，此前这两个国家曾是儿童中枢神经系统疟疾的研究对象。 美国国立卫生研究院 (NIH) 资助的合作项目帮助开发了开展临床试验所需的大量基础设施。 这种性质的校准试验。