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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.
 
ClinicalTrials.gov Identifier: NCT01660672
Recruitment Status : Completed
First Posted : August 9, 2012
Results First Posted : October 17, 2014
Last Update Posted : September 15, 2016
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Gretchen Birbeck, University of Rochester

Tracking Information
First Submitted Date  ICMJE July 19, 2012
First Posted Date  ICMJE August 9, 2012
Results First Submitted Date  ICMJE August 11, 2014
Results First Posted Date  ICMJE October 17, 2014
Last Update Posted Date September 15, 2016
Study Start Date  ICMJE January 2013
Actual Primary Completion Date July 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 16, 2014)
Freedom From Seizure [ Time Frame: 24 hours ]
Number of subjects free of seizure at 24 hours after initiation of treatment
Original Primary Outcome Measures  ICMJE
 (submitted: August 6, 2012)
Freedom From Seizure [ Time Frame: 24 hours ]
freedom from seizure of 75% of subjects for 24 hours after initiation of treatment
Change History Complete list of historical versions of study NCT01660672 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2014)
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2012)
  • Toxicity [ 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.
  • Plasma concentration of LVT [ Time Frame: 72 hours ]
    Plasma LVT concentrations will be determined through HPLC method at eight timepoints post administration to evaluate LVT absorption and elimination in pediatric CM.
Current Other Pre-specified Outcome Measures
 (submitted: October 16, 2014)
  • Number of Participants With Neurologic Sequelae at Discharge [ Time Frame: day 7 ]
    Number of participants with neurologic sequelae at discharge
  • 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.
  • 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.
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: August 6, 2012)
  • Number and type of neurologic sequelae at discharge [ Time Frame: day 7 ]
    Number and type of neurologic sequelae at discharge
  • Number of Subjects With Retinopathy at Enrollment [ Time Frame: 24 hours ]
    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 ]
    Pre-enrollment exposure to phenobarbitone may impact LVT efficacy, and analysis base on this characteristic will be evaluated.
  • Type and amount of anti-epileptic drugs required during admission [ Time Frame: 7 days ]
    The AEDs required (including for breakthrough seizures in the LVT group) during admission including the type and overall quantity received
  • 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.
 
Descriptive Information
Brief Title  ICMJE Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria
Official Title  ICMJE A Dose-Escalation, Safety And Feasibility Study Of Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria
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.
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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Seizure
  • Epilepsy
  • Cerebral Malaria
Intervention  ICMJE 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
Study Arms  ICMJE LEVETIRACETAM
Open label, dose escalation to optimal dose.
Intervention: Drug: LEVETIRACETAM
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 16, 2013)
7
Original Estimated Enrollment  ICMJE
 (submitted: August 6, 2012)
30
Actual Study Completion Date  ICMJE July 2013
Actual Primary Completion Date July 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 6 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Malawi
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01660672
Other Study ID Numbers  ICMJE LVT1R01NS074409
1R01NS074409-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gretchen Birbeck, University of Rochester
Study Sponsor  ICMJE University of Rochester
Collaborators  ICMJE National Institute of Neurological Disorders and Stroke (NINDS)
Investigators  ICMJE
Principal Investigator: Gretchen L Birbeck, M.D. University of Rochester
PRS Account University of Rochester
Verification Date August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP