An MRI ancillary study of malaria fever control RCT

Despite eradication efforts, ~400,000 African children sustained brain injuries as a result of central nervous system (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. 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 from 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 the 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. In providing early evidence of brain injury, this MRI ancillary study may also further inform global malaria care guidelines and the design of future RCTs. temperature reduction.

Project details

Diagnostics

Mar 2020 — Jan 2025

$1.09M

Malawi
Zambia

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