Clinical trial NCT01660672: Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria
Official title: A Dose-Escalation, Safety And Feasibility Study Of Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Seizure
Epilepsy
Cerebral Malaria
Lead sponsor: University of Rochester
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2012-08-09
Enrollment: 7
Sex: ALL
Minimum age (years): 2
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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

Eligibility criteria: Inclusion Criteria:

* Comatose with Blantyre Comas Score ≤ 3
* P. falciparum parasitemia
* Active seizure

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

Primary outcomes:
measure: Freedom From Seizure
timeFrame: 24 hours
Secondary outcomes:
measure: Toxicity Related to LVT
timeFrame: 1 week
measure: Range of Plasma Concentration of LVT Across All Individuals
timeFrame: 72 hours
Other outcomes:
measure: Number of Participants With Neurologic Sequelae at Discharge
timeFrame: day 7
measure: Number of Subjects With Retinopathy at Enrollment
timeFrame: Upon admission
measure: Number of Subjects Exposed to Phenobarbitone Prior to Enrollment
timeFrame: 0 hour
measure: Number of Participants Requiring AED During Admission
timeFrame: 7 days
measure: Mean Time to Return to a BCS Score Greater Than or Equal to 4
timeFrame: 7 days
Locations:
city: Blantyre
country: Malawi
facility: Queen Elizabeth Central Hospital
Study officials:
affiliation: University of Rochester
name: Gretchen L Birbeck, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Birbeck GL, Herman ST, Capparelli EV, Dzinjalamala FK, Abdel Baki SG, Mallewa M, Toto NM, Postels DG, Gardiner JC, Taylor TE, Seydel KB. A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria. BMC Pediatr. 2019 Nov 1;19(1):399. doi: 10.1186/s12887-019-1766-2.