Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria
Condition: Seizure; Epilepsy; Cerebral Malaria
MeSH terms: Malaria; Malaria, Cerebral; Seizures
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Pediatric cerebral malaria (CM) affects more than 3 million children each year killing ~20%
      and leaving one third of survivors with long term neurologic and psychiatric sequelae.
      Seizures occur commonly with CM and are associated with an increased risk of death and
      neuropsychiatric disabilities. In this Malawi-based, dose- escalation, safety and feasibility
      study of enteral levetiracetam in pediatric CM, the investigators will lay the groundwork for
      future efficacy studies aimed at improving seizure control and ultimately decreasing the
      neurologic morbidity of pediatric CM.
    

Detailed description: 
      Cerebral malaria (CM) affects ~3 million children each year, primarily in sub-Saharan Africa.
      Antimalarial medications can rapidly clear P. falciparum parasites, but mortality rates
      remain high (12-25%). Survivors do not escape unscathed--~30% experience neurologic sequelae
      including epilepsy, behavioral disorders and gross neurologic deficits. Acute seizures occur
      commonly in CM and are associated with higher neurologic morbidity and mortality. Seizure
      management in malaria endemic regions is challenging because the available antiepileptic
      drugs (AED) induce respiratory suppression and assisted ventilation is unavailable. More
      optimal seizure control may improve neurologic outcomes in pediatric CM survivors, especially
      if the medication used is affordable and can be delivered safely and easily in resource
      limited settings. The investigators propose to conduct a dose- escalation, safety and
      feasibility study of enteral levetiracetam (LVT) for seizure control in children with CM and
      seizures admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Enteral LVT given
      via nasogastric tube (NGT) rather than an intravenous (IV) formulation will be used since LVT
      has excellent enteral bioavailability and IV formations are not affordable in most
      malaria-endemic regions. LVT will be escalated based upon efficacy and toxicity endpoints
      with efficacy defined as seizure freedom in 75% of children during the 24 hours post LVT
      administration. Generally, only ~20% of children admitted with CM and seizures who receive
      standard AED treatment remain seizure free during the first 24 hours after admission. Safety
      assessments will include monitoring for problems related to NGT placement and medication
      delivery, laboratory parameters at 24 hours and 7 days post LVT, and overall case fatality
      rates. If efficacy endpoints are not met but enteral LVT is otherwise tolerated, LVT doses of
      ~3 times the standard dose used for other seizure-related conditions will be assessed.
      Pharmacokinetic (Pk) data on the absorption and elimination of LVT in CM will be obtained
      since enteral formulations are not typically used in critically ill children and malaria has
      been shown to impact drug absorption and elimination for some other medications. The safety,
      feasibility, Pk, optimal dosing and preliminary efficacy data from this proposed work will
      provide the information needed to determine whether to proceed with a randomized clinical
      trial of LVT in pediatric CM patients which would include acute seizure control as well as
      long term neurologic outcomes as critical endpoints. Since enteral LVT is relatively
      affordable for short-term use and could be feasibly delivered in resource limited settings,
      this therapy could potentially be scaled up for broad use throughout malaria endemic African
      countries
    

Intervention name(s): LEVETIRACETAM
Intervention type(s): Drug
Intervention description(s): liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose. If primary outcome is not reached, dose escalation to 150, 225, and 300% standard, as needed, will be conducted.
Other intervention name(s): Keppra
Intervention MeSH terms: Levetiracetam
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment