A Dose-Escalation, Safety and Feasibility Study of Enteral Levetiracetam for Seizure Control in Pediatric Cerebral Malaria

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by University of Rochester
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Gretchen Birbeck, University of Rochester
ClinicalTrials.gov Identifier:
NCT01982812
First received: November 5, 2013
Last updated: July 17, 2014
Last verified: July 2014
  Purpose

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
Seizure
Epilepsy
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

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


Study Start Date: January 2014
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ORAL LEVITERACETAM
Oral Leviteracetam 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.

  Eligibility

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

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Contacts
Contact: Gretchen L. Birbeck, MD 517-275-7311 gretchen_birbeck@urmc.rochester.edu
Contact: Roseanna Battista 525-275-1642 Roseanna.Battista@chet.rochester.edu

Locations
Malawi
Queen Elizabeth Central Hospital Recruiting
Blantyre, Malawi, 3
Contact: Esther Gondwe    265-0-9-969222    egondwe@gmail.com   
Contact: Neema Mtunthama    265-(0)999 981451    nmtunthama@yahoo.com   
Principal Investigator: Gretchen Birbeck, M.D.         
Sponsors and Collaborators
University of Rochester
Investigators
Principal Investigator: Gretchen L Birbeck, M.D. University of Rochester
  More Information

No publications provided

Responsible Party: Gretchen Birbeck, Professor, University of Rochester
ClinicalTrials.gov Identifier: NCT01982812     History of Changes
Other Study ID Numbers: 7 R01 NS074409-02
Study First Received: November 5, 2013
Last Updated: July 17, 2014
Health Authority: Study Monitoring Committee Malawi:
Malawi's Pharmacy Medicines and Poisons Board (PMPB)Malawi:

Additional relevant MeSH terms:
Central Nervous System Protozoal Infections
Protozoan Infections
Malaria
Malaria, Cerebral
Seizures
Brain Diseases
Central Nervous System Diseases
Central Nervous System Infections
Central Nervous System Parasitic Infections
Epilepsy
Malaria, Falciparum
Nervous System Diseases
Neurologic Manifestations
Parasitic Diseases
Signs and Symptoms
Etiracetam
Anticonvulsants
Central Nervous System Agents
Nootropic Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014