A Safety and Feasibility Study of Enteral LVT vs. Standard of Care for Seizure Control in Pediatric CM

Study Overview
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Brief Summary
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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, 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
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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 conducted a dose- escalation study detailed elsewhere (NCT01660672) to determine the optimal dose for use in this 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 40mg/kg followed by 30mg per kg Q12 hourly. Children admitted with cerebral malaria and seizures will be randomized to LVT vs. standard of care with phenobarbital as needed comparing seizure control, safety, and neurological outcomes.

Official Title
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A Safety and Feasibility Study of Enteral Levetiracetam vs. Phenobarbital for Seizure Control in Pediatric Cerebral Malaria

Conditions
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Seizure, Epilepsy, Cerebral Malaria

Intervention / Treatment
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* Drug: Oral Levetiracetam
* Drug: Standard AED


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Comatose with Blantyre Comas Score ≤ 2 P. falciparum parasitemia via thick blood film or rapid diagnostic test Active seizure in past 24 hours Exclusion Criteria: Serum creatinine > 2mg/dL Pre-admission/concomitant treatment with antiretroviral medications for HIV (ARVs), antituberculous treatments(ATTs), or chronic use of any other enzyme-inducing medications

Ages Eligible for Study
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Minimum Age: 24 Months
Maximum Age: 83 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Levetiracetam<br>Oral Levetiracetam administered by NG tube. | Drug: Oral Levetiracetam<br>* liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days<br>* Other names: Keppra;|
| Active Comparator: Standard AED<br>Standard AED regimen | Drug: Standard AED<br>* Active comparitor, Standard AED<br>* Other names: Standard regimen of AED therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minutes With Seizure on EEG | Comparing LVT to standard AED the number of minutes spent in seizure per cEEG in the 72 hours after treatment allocation. | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Required Additional AED | Additional AEDs required (including for breakthrough seizures in LVT group) during admission for seizure control (yes/no) | 7 days | 
| Mean Time From Admission to BCS >/= 4 | The mean time in hours from admission until the subject reaches Blantyre Coma Scale of greater than or equal to 4. Participants who died are excluded from this analysis. The Blantyre Coma Score has ranges from 0-5 based upon the a sum of the following 3 domains- Eye movement 1 - Watches or follows 0 - Fails to watch or follow Best motor response 2 - Localizes painful stimulus 1 - Withdraws limb from painful stimulus 0 - No response or inappropriate response Best verbal response 2 - Cries appropriately with pain, or, if verbal, speaks 1 - Moan or abnormal cry with pain 0 - No vocal response to pain | 7 days | 
| Sequelae | Neurologic outcome in 3 categories-- Neurologically intact at discharge Neurologic sequelae at discharge--specifically new sensory or motor deficits, ongoing seizures, or behavioral abnormalities based upon a physician examination at discharge Died during admission, never discharged | 7 days |