A Dose-Escalation, Safety and Feasibility Study of Enteral LVT for Seizure Control in Pediatric CM
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.
Drug: Oral Levetiracetam
Drug: Standard AED
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Dose-Escalation, Safety and Feasibility Study of Enteral Levetiracetam for Seizure Control in Pediatric Cerebral Malaria|
- Minutes with seizure on EEG [ Time Frame: 72 hours ] [ Designated as safety issue: No ]Comparing LVT to standard AED the number of minutes spent in seizure per cEEG in the 72 hours after treatment allocation.
- The AEDs required during admission [ Time Frame: 7 days ] [ Designated as safety issue: No ]The AEDs required (including for breakthrough seizures in LVT group) during admission includ-ing agent(s) and overall quantity received
- Mean time from admission to BCS >/= 4 [ Time Frame: 7 days ] [ Designated as safety issue: No ]The mean time from admission to the subject reaches Blantyre Coma Scale of greater than or equal to 4
- Sequelae [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]Neurologic sequelae at discharge
|Study Start Date:||January 2014|
|Study Completion Date:||June 2015|
|Primary Completion Date:||June 2015 (Final data collection date for primary outcome measure)|
Experimental: Oral Levetiracetam
Oral Levetiracetam administered by NG tube.
Drug: Oral Levetiracetam
liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days
Other Name: Keppra
Active Comparator: Standard AED
Standard AED regimen
Drug: Standard AED
Active comparitor, Standard AED
Other Name: Standard regimen of AED therapy
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01982812
|Queen Elizabeth Central Hospital|
|Blantyre, Malawi, 3|
|Principal Investigator:||Gretchen L Birbeck, M.D.||University of Rochester|