Aggressive Antipyretics for Fever Reduction in CNS Malaria
Condition: Malaria; Seizures; Coma; Parasitemia; Hyperpyrexia; Fever
MeSH terms: Malaria; Parasitemia; Seizures; Fever; Hyperthermia
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Acetaminophen; Ibuprofen; placebo for acetaminophen; placebo for ibuprofen
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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; 10 mg/kg Q6 hours for the Aggressive Antipyretic Arm; 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; placebo for ibuprofen
Other intervention name(s): Paracetamol; Brufen; Placebo; Placebo
Intervention MeSH terms: Acetaminophen; Ibuprofen
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: HRP2