Aggressive antipyretics for neuroprotection and mortality reduction in CNS malaria: A Randomized-Controlled Trial - Despite ongoing eradication and vaccination efforts, brain injury from severe malaria caused over 430,000 deaths among African children in 2023. Beyond the body count, up to a third of survivors of malaria involving the central nervous system (CNS) experience sequelae including neurodisabilities and epilepsy. These injuries occur in children who survive cerebral malaria, meaning severe malaria with deep coma, but they also occur in children with CNS involvement without deep coma including less severe impairment of consciousness and complicated seizures. This broader spectrum of malaria impacting the nervous system is termed `CNS malaria' with cerebral malaria being the most severe form. Standard of care with artesunate provides rapid parasite clearance, but for children with CNS malaria the persistent, pro-inflammatory response to parasite sequestration within the cerebral vasculature and the associated local hypoxia, blood brain barrier breakdown, seizures, hyperpyrexia and brain swelling requires the development of adjunctive therapies. In this planning grant, our research consortium working in Malawi, Zambia and the Democratic Republic of Congo (DRC) will conduct preparations to facilitate the successful launch of a multi-national, randomized, controlled trial of adjunctive aggressive antipyretic (AAA) therapy to reduce mortality and neurological morbidity in children with CNS malaria. A recent randomized, blinded, placebo-controlled, trial of AAA therapy with scheduled, maximal dose, ibuprofen plus acetaminophen showed AAA therapy reduced the severity of both fevers and seizures in pediatric CNS malaria. This study also suggested some signal for a decrease in mortality. Some neuroinflammatory biomarkers associated with malaria disease severity were also reduced at 24 hours in the AAA treated children compared to those receiving usual care. In this R34 proposed, phase III AAA malaria study, children 2-11 years of age with CNS malaria will be randomized to receive AAA treatment for 72 hours vs usual care which includes standard dose acetaminophen for fevers of ≥38.5° Celsius. Children with moderate or worse acute kidney injury (creatinine >1.2 mg/dL) and those screening positive for pre-existing neurodisabilities or epilepsy will be excluded. The primary outcome will be the time from randomization to either death, occurrence of a moderate-to-severe neurodisability, or epilepsy, whichever occurs first. During this R34, logistical preparations will be undertaken including capacity building for neurological outcome assessments in DRC. All sites will undertake translation and piloting of outcomes instruments. The protocol, statistical analysis plan and manual of procedures will be finalized and regulatory approvals will be sought. During the conduct of this R34, an application for an extended clinical trial (PAR-23- 084) will be submitted to facilitate a smooth transition to conducting the planned, phase III clinical trial of AAA therapy. Acetaminophen and ibuprofen are inexpensive, widely available agents and thus may offer an affordable, sustainable approach to neuroprotection in severe malaria.
