Aggressive Antipyretics in CNS Malaria: Study Protocol of a Randomized-Controlled Trial Assessing Antipyretic Efficacy and Parasite Clearance Effects (Malaria FEVER Study)

Abstract

AbstractBackgroundDespite 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. Evidence indicates that among children with CNS malaria, a higher temperature during the acute illness is a risk factor for post-infectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted, at least among children with complicated malaria who are at substantial risk of brain injury. Previous clinical trials conducted primarily 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 using dual therapies. In this clinical trial of aggressive antipyretic therapy, children hospitalized with CNS malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature ≥ 38.5°C) 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.MethodsWe will enroll 284 participants from three settings at Queen Elizabeth Central Hospital in Blantyre, Malawi; at the University Teaching Hospitals Children’s Hospital in Lusaka, Zambia and at Chipata Central Hospital, Chipata, Zambia. Parents or guardians must provide written informed consent. Eligible participants are 2-11 years with evidence of P. falciparum malaria infection by peripheral blood smear or rapid diagnostic test with CNS symptoms associated with malaria. Eligible children will receive treatment allocation as determined by randomization and will be assigned to treatment groups with 1:1 allocation using blocked randomization.DiscussionThe clinical trial proposed here seeks to challenge the practice paradigm of limited fever treatment based upon hyperpyrexia by evaluating the fever-reduction efficacy of more aggressive antipyretic use involving two antipyretics and prophylactic administration while also taking advantage of a relatively new method for quantifying total parasite burden (HRP2 quantification) to further characterize malaria severity and elucidate the impact of antipyretics on parasite sequestration and clearance. If aggressive antipyretic therapy is shown to safely reduce the maximum temperature during CNS malaria, a clinical trial evaluating the neuroprotective effects of temperature reduction in CNS malaria is warranted.Trial registrationThis trial is registered with ClinicalTrial.gov (NCT03399318) and with the Pan African Clinical Trials Registry (PACTR201804003255157)