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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01660672
Recruitment Status : Completed
First Posted : August 9, 2012
Results First Posted : October 17, 2014
Last Update Posted : September 15, 2016
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Gretchen Birbeck, University of Rochester

Brief 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.

Condition or disease Intervention/treatment Phase
Seizure Epilepsy Cerebral Malaria Drug: LEVETIRACETAM Phase 1 Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Dose-Escalation, Safety And Feasibility Study Of Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria
Study Start Date : January 2013
Actual Primary Completion Date : July 2013
Actual Study Completion Date : July 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria Seizures

Arm Intervention/treatment
Open label, dose escalation to optimal dose.
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 Name: Keppra

Primary Outcome Measures :
  1. Freedom From Seizure [ Time Frame: 24 hours ]
    Number of subjects free of seizure at 24 hours after initiation of treatment

Secondary Outcome Measures :
  1. Toxicity Related to LVT [ Time Frame: 1 week ]
    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.

  2. Range of Plasma Concentration of LVT Across All Individuals [ Time Frame: 72 hours ]
    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.

Other Outcome Measures:
  1. Number of Participants With Neurologic Sequelae at Discharge [ Time Frame: day 7 ]
    Number of participants with neurologic sequelae at discharge

  2. Number of Subjects With Retinopathy at Enrollment [ Time Frame: Upon admission ]
    Retinopathy status may impact LVT efficacy and subject status will be analyzed based on this characteristic.

  3. Number of Subjects Exposed to Phenobarbitone Prior to Enrollment [ Time Frame: 0 hour ]
    Pre-enrollment exposure to phenobarbitone may impact LVT efficacy, and analysis base on this characteristic will be evaluated.

  4. Number of Participants Requiring AED During Admission [ Time Frame: 7 days ]
    Number of participants who required AEDS during admission(including for breakthrough seizures in the LVT group) during admission.

  5. Mean Time to Return to a BCS Score Greater Than or Equal to 4 [ Time Frame: 7 days ]
    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.

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Ages Eligible for Study:   2 Years to 6 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01660672

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Queen Elizabeth Central Hospital
Blantyre, Malawi, 3
Sponsors and Collaborators
University of Rochester
National Institute of Neurological Disorders and Stroke (NINDS)
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Principal Investigator: Gretchen L Birbeck, M.D. University of Rochester
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Gretchen Birbeck, Professor, University of Rochester Identifier: NCT01660672    
Other Study ID Numbers: LVT1R01NS074409
1R01NS074409-01A1 ( U.S. NIH Grant/Contract )
First Posted: August 9, 2012    Key Record Dates
Results First Posted: October 17, 2014
Last Update Posted: September 15, 2016
Last Verified: August 2016
Additional relevant MeSH terms:
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Malaria, Cerebral
Central Nervous System Diseases
Nervous System Diseases
Protozoan Infections
Parasitic Diseases
Neurologic Manifestations
Central Nervous System Protozoal Infections
Central Nervous System Parasitic Infections
Central Nervous System Infections
Nootropic Agents