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.

尽管持续的根除努力，但疟疾仍然是非洲的主要公共卫生挑战，每年， 〜250,000名疟疾儿童经历了神经系统损伤，随后具有神经疾病。在其他中央 神经系统（CNS）疾病，发烧是担心继发性神经系统损伤和表现的公认原因 为避免高温或诱导神经保护症的体温过低而做出紧张的努力。证据表明 在中枢神经系统疟疾患者中，急性疾病期间的温度更高，是后期后的风险因素 机构神经系统后遗症。因此，至少在Chil- 患有复杂的疟疾，脑损伤的风险很大。以前进行了临床试验 玛丽（Marily）患有简单疟疾并仅使用一种抗热药物的儿童显示有限 减少发烧方面的好处；但是，迄今为止尚无研究检查疟疾发烧管理美国 双重疗法。对照顾儿童的临床医生侵略性发烧措施的热情 疟疾通过体外发现抑制了疟疾寄生虫复制在较高温度下变慢 以及一项单一的临床试验，在接受FE-的儿童中，外围寄生虫清除率较慢 ver。但是，温度与疟疾寄生虫行为之间的关系很复杂。额外的体外 数据表明，在高温温度下，未感染的红细胞（RBC）更有可能遵守感染 RBC，担心隔离过程，增加了寄生虫伯嫩阻塞微血管典写的 BRAL血流，也许有助于中枢神经系统疟疾中持续的免疫致病发生。在此探索性中 侵略性抗热治疗的临床试验，患有中枢神经系统疟疾的儿童将随机分配给常规 护理（对乙酰氨基酚每6小时，温度≥38.5ºC）与预防性对乙酰氨基酚和布洛芬 每6小时每6小时，持续72小时。这项概念验证研究将确定是否侵略性抗热治疗 相对于通常的护理，导致平均最高温度较低。 HRP2的序列定量水平，fal- CIPARUM特异性蛋白促进了全身寄生虫Burnen和CNS寄生虫secestra-的估计值 还将收集tion，以阐明抗热用的使用与体内寄生虫行为之间的关系。寻找- 这项研究的INS将确定侵袭性抗热药的III期临床试验是否用于神经保护作用 应该进行小儿中枢神经系统疟疾。这项研究将在赞比亚和马拉维进行， NIH资助的合作有助于开发开展诊所所需的大量基础设施 这种性质的cal试验。