Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria (LVT1)

A Dose-Escalation, Safety And Feasibility Study Of Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria

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.

Study Overview

• Status: Completed
• Conditions: Epilepsy; Seizure; Cerebral Malaria
• Intervention / Treatment: Drug: LEVETIRACETAM

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

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Malawi
  • Blantyre, Malawi, 3
    • Queen Elizabeth Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 6 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: LEVETIRACETAM; Open label, dose escalation to optimal dose.	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.; Other Names: Keppra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Freedom From Seizure	Number of subjects free of seizure at 24 hours after initiation of treatment	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Neurologic Sequelae at Discharge	Number of participants with neurologic sequelae at discharge	day 7
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
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
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
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

Collaborators and Investigators

• Sponsor: University of Rochester
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Gretchen L Birbeck, M.D., University of Rochester

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: July 19, 2012
• First Submitted That Met QC Criteria: August 6, 2012
• First Posted (Estimate): August 9, 2012

Study Record Updates

• Last Update Posted (Estimate): September 15, 2016
• Last Update Submitted That Met QC Criteria: August 3, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Neurologic Manifestations; Central Nervous System Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Central Nervous System Parasitic Infections; Central Nervous System Protozoal Infections; Seizures; Malaria; Malaria, Cerebral; Anticonvulsants; Nootropic Agents; Levetiracetam
• Other Study ID Numbers: LVT1R01NS074409; 1R01NS074409-01A1 (U.S. NIH Grant/Contract)