A Dose-Escalation, Safety and Feasibility Study of Enteral LVT for Seizure Control in Pediatric CM

Epilepsy Clinical Trial

Official title:

A Dose-Escalation, Safety and Feasibility Study of Enteral Levetiracetam for Seizure Control in Pediatric Cerebral Malaria

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01982812
• Other study ID #: 7R01NS074409-02
• Secondary ID: R01NS074409
• Status: Completed
• Phase: Phase 2
• First received: November 5, 2013
• Last updated: June 19, 2015
• Start date: January 2014
• Est. completion date: June 2015

Study information

• Verified date: June 2015
• Source: University of Rochester
• Contact: n/a
• Is FDA regulated: No
• Health authority: Study Monitoring Committee Malawi:Malawi's Pharmacy Medicines and Poisons Board (PMPB)Malawi:
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 24 Months to 83 Months

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cerebral Malaria
• Epilepsy
• Malaria
• Malaria, Cerebral
• Seizure
• Seizures

Intervention

Drug:
• Oral Levetiracetam
liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days
• Standard AED
Active comparitor, Standard AED

Locations

Country	Name	City	State
Malawi	Queen Elizabeth Central Hospital	Blantyre

Sponsors (2)

Lead Sponsor	Collaborator
University of Rochester	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

Malawi, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	The AEDs required during admission	The AEDs required (including for breakthrough seizures in LVT group) during admission includ-ing agent(s) and overall quantity received	7 days	No
Secondary	Mean time from admission to BCS >/= 4	The mean time from admission to the subject reaches Blantyre Coma Scale of greater than or equal to 4	7 days	No
Secondary	Sequelae	Neurologic sequelae at discharge	7 days	Yes