Aggressive Antipyretics for Fever Reduction in CNS Malaria

Aggressive Antipyretics in CNS Malaria: A Randomized-Controlled Trial Assessing Antipyretic Efficacy and Parasite Clearance Effects

The study will examine whether prophylactic and scheduled treatment with acetaminophen and ibuprofen can decrease the maximum temperature experienced during the acute illness in children with CNS malaria.

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-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. 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 fever. 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 cerebral blood flow, and perhaps contributing to ongoing immunopathogenesis 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 histidine rich protein 2 (HRP2), a P. falciparum-specific protein that facilitates estimates of whole body parasite burden and CNS parasite sequestration, will also be collected to clarify the relationship between antipyretic use and in vivo parasite behavior. Findings 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 clinical trial of this nature.

regardless of temperature, children allocated to this arm will receive acetaminophen (30 milligrams (mg)/ kilogram (kg) load then 15mg/kg Q6 hours) and ibuprofen (10mg/kg Q 6 hours) for 72 hours. Pediatric syrup formulations of both agents will be administered orally or via nasogastric tube. For temperatures over 38.5 degrees Celsius, placebo will be added and if the fever persists, a cooling fan will be added.

will receive placebo for acetaminophen and placebo for ibuprofen. If they have a temperature over 38.5 degrees Celsius, they will receive acetaminophen (15mg/kg, Q6 hours), as needed. If the fever persists, a cooling fan will be added.

30 mg/kg load then 15mg/kg Q6 hours for the Aggressive Antipyretic Arm Acetaminophen is also given to children in the placebo arm when they have a fever over 38.5 degrees Celsius during scheduled clinical assessments

placebo for acetaminophen for children in the Usual Care arm For children in the Aggressive Antipyretic Arm, when they have a temperature over 38.5 degrees Celsius they are treated with a placebo

Mean maximum temperature (TMAX). TMAX will be defined as the highest temperature during the study duration (72 hours) in degrees Celsius recorded by a continuous temperature monitor. The continuous temperature monitors are not magnetic resonance imaging (MRI) compatible. If TMAX is a clinical temperature obtained when continuous monitoring data is not available, the clinical TMAX will be used as the primary outcome.

based upon histadine rich protein 2 (HRP2) levels and quantitative blood film Q6 hourly until aparasitemic on thick blood smear

Inclusion Criteria: Evidence of Plasmodium falciparum malaria infection by peripheral blood smear or rapid diagnostic test Central nervous system (CNS) symptoms associated with malaria. CEREBRAL MALARIA (CM): Impaired consciousness with a Blantyre Coma Score (BCS)(73) ≤2 in children under 5 years or a Glasgow Coma score (GCS) ≤10 in children ≥5 years OR CNS MALARIA: Complicated seizure(s), meaning prolonged (>15 minutes), focal or multiple; or impaired consciousness or other evidence of impaired consciousness (confusion, delirium) without frank coma (BCS>2, GCS =11-14) Exclusion Criteria: Circulatory failure (cold extremities, capillary refill > 3 seconds, sunken eyes, ↓ skin turgor) Vomiting in the past 2 hours Serum creatinine (Cr) > 1.2 mg/dL A history of liver disease Jaundice or a total bilirubin of >3.0mg/dL A history of gastric ulcers or gastrointestinal bleeding A history of thrombocytopenia or other primary hematologic disorder Petechiae or other clinical indications of bleeding abnormalities A known allergy to ibuprofen, acetaminophen, aspirin or any non-steroidal medication Any contraindication for nasogastric tube (NGT) placement and/or delivery of enteral medications

Tembo D, Mwanza S, Mwaba C, Dallah I, Wa Somwe S, Seydel KB, Birbeck GL. Risk factors for acute kidney injury at presentation among children with CNS malaria: a case control study. Malar J. 2022 Nov 1;21(1):310. doi: 10.1186/s12936-022-04327-y.