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

This study has been completed.
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Gretchen Birbeck, University of Rochester
ClinicalTrials.gov Identifier:
First received: November 5, 2013
Last updated: June 19, 2015
Last verified: June 2015
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.

Condition Intervention Phase
Cerebral Malaria
Drug: Oral Levetiracetam
Drug: Standard AED
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Dose-Escalation, Safety and Feasibility Study of Enteral Levetiracetam for Seizure Control in Pediatric Cerebral Malaria

Resource links provided by NLM:

Further study details as provided by University of Rochester:

Primary Outcome Measures:
  • Minutes with seizure on EEG [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    Comparing LVT to standard AED the number of minutes spent in seizure per cEEG in the 72 hours after treatment allocation.

Secondary Outcome Measures:
  • The AEDs required during admission [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    The AEDs required (including for breakthrough seizures in LVT group) during admission includ-ing agent(s) and overall quantity received

  • Mean time from admission to BCS >/= 4 [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    The mean time from admission to the subject reaches Blantyre Coma Scale of greater than or equal to 4

  • Sequelae [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    Neurologic sequelae at discharge

Enrollment: 44
Study Start Date: January 2014
Study Completion Date: June 2015
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Keppra
Active Comparator: Standard AED
Standard AED regimen
Drug: Standard AED
Active comparitor, Standard AED
Other Name: Standard regimen of AED therapy

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.

Ages Eligible for Study:   24 Months to 83 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01982812

Queen Elizabeth Central Hospital
Blantyre, Malawi, 3
Sponsors and Collaborators
University of Rochester
National Institute of Neurological Disorders and Stroke (NINDS)
Principal Investigator: Gretchen L Birbeck, M.D. University of Rochester
  More Information

Responsible Party: Gretchen Birbeck, Professor, University of Rochester
ClinicalTrials.gov Identifier: NCT01982812     History of Changes
Other Study ID Numbers: 7R01NS074409-02  R01NS074409 
Study First Received: November 5, 2013
Last Updated: June 19, 2015
Health Authority: Study Monitoring Committee Malawi:
Malawi's Pharmacy Medicines and Poisons Board (PMPB)Malawi:

Additional relevant MeSH terms:
Malaria, Cerebral
Brain Diseases
Central Nervous System Diseases
Central Nervous System Infections
Central Nervous System Parasitic Infections
Central Nervous System Protozoal Infections
Malaria, Falciparum
Nervous System Diseases
Neurologic Manifestations
Parasitic Diseases
Protozoan Infections
Signs and Symptoms
Central Nervous System Agents
Neuroprotective Agents
Nootropic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 27, 2016