An MRI Ancillary Study of Malaria Fever Control RCT

疟疾发热控制的 MRI 辅助随机对照试验

• 批准号: 10556361
• 负责人: GRETCHEN L. BIRBECK
• 金额: $ 24.55万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556361
• 关键词: Acetaminophen; Acute; Adverse effects; Adverse event; Affect; African; Age; Ancillary Study; Anti-Inflammatory Agents; Antiinflammatory Effect; Autopsy; Behavior assessment; Blinded; Blood; Blood Platelets; Brain; Brain Injuries; Caring; Child; Child Care; Childhood; Clinical Treatment; Clinical Trials; Clinical Trials Data Monitoring Committees; Data; Early identification; Enrollment; Evaluation; Evolution; Fever; Future; Goals; Guidelines; Hemorrhage; Hemosiderin; Ibuprofen; Image; Infrastructure; Injury; Intervention; Intervention Trial; Intraventricular; Lesion; Link; Location; Longterm Follow-up; Magnetic Resonance Imaging; Malaria; Malawi; Mediating; Methods; Negative Finding; Neurologic; Neurological outcome; Outcome; Pathway interactions; Phase; Population; Prevalence; Property; Proxy; Randomized, Controlled Trials; Recovery; Research; Research Design; Residual state; Risk; Risk Factors; Severities; Stains; Structural defect; Temperature; Zambia; acute infection; antipyretic; blood product; brain abnormalities; cognitive testing; design; follow-up; insight; malaria infection; neuroimaging; neuroprotection; primary outcome; programs; radiologist; routine care; scale up; tool; treatment as usual; treatment response; treatment stratification; treatment-related injury

Contact PD/PI: BIRBECK, GRETCHEN L. ABSTRACT Despite eradication efforts, ~400,000 African children sustained brain injuries as a result of CNS malaria in 2016. A higher maximum temperature (Tmax) during the acute malaria infection is an established risk factor for neurologic sequelae and a randomized controlled trial (RCT) of aggressive antipyretic therapy with acetaminophen and ibuprofen began enrollment in Malawi in 2019 (R01NS102176) with expansion into Zambia pending. In this clinical trial, the primary outcome is Tmax during the acute infection. However, the antipyretic therapies used in this RCT may offer neuroprotective benefits without affecting Tmax--for example, neuroprotection through anti-inflammatory mechanisms. In this ancillary study, we propose to use neuroimaging in the context of the RCT to further evaluate the potential neuroprotective effects of aggressive antipyretic therapy for CNS malaria and explore possible mechanisms for these effects. Comparing children allocated to aggressive antipyretic therapy vs. usual care on the prevalence of structural brain abnormalities after recovery from CNS malaria will facilitate the evaluation of non-fever pathways for neuroprotection. Both Zambia and Malawi have an unusually well developed infrastructure for advanced imaging in the academic Brain MRIs will be obtained in children enrolled in the RCT at 1- and 12-months post recovery. Analyses will be completed comparing the odds of having any structural injury based upon RCT treatment allocation and based upon (Tmax) stratified by treatment allocation to assess changes specifically related to response to therapy in terms of fever reduction. Potential mechanisms of aggressive antipyretic-related injury will be evaluated including assessments for treatment-related CNS bleeds. Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury including in pediatric CNS malaria. Adding this MRI ancillary study to our fever RCT may elucidate mechanisms of treatment-associated injury and allow for early identification of neuroprotection from aggressive antipyretic use that would otherwise require long-term follow-up for cognitive and behavioral assessments. This MRI ancillary study when added to the Fever RCT will provide critical insights that could inform future neuroprotective studies of malaria that might incorporate imaging to optimize study design. centers where the RCT using aggressive antipyretic therapy will be conducted. Page 7 Project Summary/Abstract

联系PD/PI：BIRBECK，Gretchen L. 摘要 尽管有根除疟疾的努力，但在非洲，仍有约40万名非洲儿童因中枢神经系统疟疾而遭受脑损伤。 2016.急性疟疾感染期间较高的最高温度（Tmax）是一个确定的危险因素， 神经系统后遗症和一项随机对照试验（RCT）的积极解热治疗， 对乙酰氨基酚和布洛芬于2019年开始在马拉维招募（R 01 NS 102176），并扩展到 赞比亚待定。在这项临床试验中，主要结局是急性感染期间的Tmax。但 在该RCT中使用的退热疗法可以提供神经保护益处而不影响Tmax-例如， 通过抗炎机制进行神经保护。在这项辅助研究中，我们建议使用 在RCT的背景下进行神经影像学检查，以进一步评估侵袭性神经保护剂的潜在神经保护作用。 中枢神经系统疟疾的解热治疗并探索这些作用的可能机制。比较儿童 分配到积极的解热治疗与常规护理对结构性脑异常的患病率 在从CNS疟疾中恢复后，将有助于评估用于神经保护的非发热途径。两 赞比亚和马拉维在学术领域的先进成像方面拥有异常发达的基础设施， 脑部MRI将于 在恢复后1个月和12个月入组RCT的儿童。将完成分析， 基于RCT治疗分配和基于（Tmax）分层的任何结构性损伤的几率 治疗分配，以评估与治疗反应（发热减少）特别相关的变化。 将评价侵袭性解热相关损伤的潜在机制，包括评估 治疗相关CNS出血。神经影像学检查是一种公认的、有效的神经功能结局替代方法， 脑损伤，包括小儿中枢神经系统疟疾。将该MRI辅助研究添加到我们的发热RCT中， 治疗相关损伤的机制，并允许早期识别神经保护， 使用退烧药，否则需要长期随访进行认知和行为评估。这 将MRI辅助研究添加到发热RCT中时，将提供重要见解，可为未来的研究提供信息。 疟疾的神经保护研究可能会结合成像来优化研究设计。 将进行使用积极退热治疗的RCT的中心。 第7页 项目总结/摘要