Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Gretchen Birbeck, University of Rochester
ClinicalTrials.gov Identifier:
NCT01660672
First received: July 19, 2012
Last updated: October 16, 2014
Last verified: October 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: LEVETIRACETAM
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group 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:
  • Freedom From Seizure [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
    Number of subjects free of seizure at 24 hours after initiation of treatment


Secondary Outcome Measures:
  • Toxicity Related to LVT [ Time Frame: 1 week ] [ Designated as safety issue: Yes ]
    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.

  • Range of Plasma Concentration of LVT Across All Individuals [ Time Frame: 72 hours ] [ Designated as safety issue: No ]
    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:
  • Number of Participants With Neurologic Sequelae at Discharge [ Time Frame: day 7 ] [ Designated as safety issue: No ]
    Number of participants with neurologic sequelae at discharge

  • Number of Subjects With Retinopathy at Enrollment [ Time Frame: Upon admission ] [ Designated as safety issue: No ]
    Retinopathy status may impact LVT efficacy and subject status will be analyzed based on this characteristic.

  • Number of Subjects Exposed to Phenobarbitone Prior to Enrollment [ Time Frame: 0 hour ] [ Designated as safety issue: No ]
    Pre-enrollment exposure to phenobarbitone may impact LVT efficacy, and analysis base on this characteristic will be evaluated.

  • Number of Participants Requiring AED During Admission [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    Number of participants who required AEDS during admission(including for breakthrough seizures in the LVT group) during admission.

  • Mean Time to Return to a BCS Score Greater Than or Equal to 4 [ Time Frame: 7 days ] [ Designated as safety issue: No ]
    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.


Enrollment: 7
Study Start Date: January 2013
Study Completion Date: July 2013
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Keppra

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:   2 Years to 6 Years
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: NCT01660672

Locations
Malawi
Queen Elizabeth Central Hospital
Blantyre, Malawi, 3
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: NCT01660672     History of Changes
Other Study ID Numbers: LVT1R01NS074409, 1R01NS074409-01A1
Study First Received: July 19, 2012
Results First Received: August 11, 2014
Last Updated: October 16, 2014
Health Authority: Study Monitoring Committee Malawi:
Malawi's Pharmacy Medicines and Poisons Board (PMPB)Malawi:

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

ClinicalTrials.gov processed this record on November 25, 2014