A Safety and Feasibility Study of Enteral LVT vs. Standard of Care for Seizure Control in Pediatric CM (LVT2)

A Safety and Feasibility Study of Enteral Levetiracetam vs. Phenobarbital 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, 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: Oral Levetiracetam; Drug: Standard AED

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 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.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

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 ≤ 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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

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, 2014
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: November 5, 2013
• First Submitted That Met QC Criteria: November 5, 2013
• First Posted (Estimate): November 13, 2013

Study Record Updates

• Last Update Posted (Estimate): July 29, 2016
• Last Update Submitted That Met QC Criteria: June 20, 2016
• Last Verified: June 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: 7R01NS074409-02 (U.S. NIH Grant/Contract); R01NS074409 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After the finding have been published, the de-identified study data will be available to other researchers on request pending a review of their plans for using the data.