Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria

Epilepsy Clinical Trial

— LVT1  

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: NCT01660672
• Other study ID #: LVT1R01NS074409
• Secondary ID: 1R01NS074409-01A
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: July 19, 2012
• Last updated: October 16, 2014
• Start date: January 2013
• Est. completion date: July 2013

Study information

• Verified date: October 2014
• 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: 7
• Est. completion date: July 2013
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 6 Years

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• LEVETIRACETAM
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.

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
Other	Number of Participants With Neurologic Sequelae at Discharge	Number of participants with neurologic sequelae at discharge	day 7	No
Other	Number of Subjects With Retinopathy at Enrollment	Retinopathy status may impact LVT efficacy and subject status will be analyzed based on this characteristic.	Upon admission	No
Other	Number of Subjects Exposed to Phenobarbitone Prior to Enrollment	Pre-enrollment exposure to phenobarbitone may impact LVT efficacy, and analysis base on this characteristic will be evaluated.	0 hour	No
Other	Number of Participants Requiring AED During Admission	Number of participants who required AEDS during admission(including for breakthrough seizures in the LVT group) during admission.	7 days	No
Other	Mean Time to Return to a BCS Score Greater Than or Equal to 4	Mean time from admission to a BCS score greater than or equal to 4. The BCS (Blantyre Coma Scale) is a 0-5 scale measuring motor response, verbal response and eye movement assessing the severity of coma in children with cerebral malaria. Lower scores correspond to more profound coma.	7 days	No
Primary	Freedom From Seizure	Number of subjects free of seizure at 24 hours after initiation of treatment	24 hours	No
Secondary	Toxicity Related to LVT	Toxicity including vomiting, aspiration, complications related to the NGT, laboratory parameters at 24 hours and 1 week post LVT administration, and an overall acute case fatality rate significantly above the consistent historical ward average for CM. Pk studies to evaluate LVT absorption and elimination in pediatric CM.	1 week	Yes
Secondary	Range of Plasma Concentration of LVT Across All Individuals	Range of plasma LVT concentrations will be determined through HPLC method at eight timepoints post administration to evaluate LVT absorption and elimination in pediatric CM.	72 hours	No