Established Status Epilepticus Treatment Trial

Overview

The primary objective is to determine the most effective and/or the least effective treatment of benzodiazepine-refractory status epilepticus (SE) among patients older than 2 years. There are three active treatment arms being compared: fosphenytoin (FOS),levetiracetam (LEV), and valproic acid (VPA). The second objective is comparison of three drugs with respect to secondary outcomes. The final objective is to ensure that the trial is informative for treatment of established SE in children by describing the effectiveness, safety, and rate of adverse reactions of these drugs in children.

Full Title of Study: “A Multicenter, Randomized, Blinded, Comparative Effectiveness Study of Fosphenytoin, Valproic Acid, or Levetiracetam in the Emergency Department Treatment of Patients With Benzodiazepine-refractory Status Epilepticus.”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: February 2019

Interventions

  • Drug: Fosphenytoin
  • Drug: Levetiracetam
  • Drug: Valproic acid

Arms, Groups and Cohorts

  • Active Comparator: Fosphenytoin (FOS)
    • Administer 20 mg/Kg fosphenytoin intravenously up to a maximum dose of 1500 mg ( 75 Kg) over 10 minutes. Those weighing more than 75 Kg receive a fixed dose of 1500 fosphenytoin over 10 minutes.
  • Active Comparator: Valproic acid
    • Administer 40 mg/Kg valproic acid intravenously up to a maximum dose of 3000 mg (75 Kg) over 10 minutes. Those weighing more than 75 Kg receive a fixed dose of 3000 valproic acidover 10 minutes.
  • Active Comparator: Levetiracetam
    • Administer 60 mg/Kg levetiracetam intravenously up to a maximum dose of 4500 mg ( 75 Kg) over 10 minutes. Those weighing more than 75 Kg receive a fixed dose of 4500 levetiracetam over 10 minutes.

Clinical Trial Outcome Measures

Primary Measures

  • Number of Participants With Clinical Cessation of Status Epilepticus – Intention to Treat
    • Time Frame: Within 60 minutes after the start of study drug infusion
    • Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. Intention to treat
  • Number of Participants With Clinical Cessation of Status Epilepticus – Per-protocol Analysis
    • Time Frame: Within 60 minutes after the start of study drug infusion
    • Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. Per-protocol analysis
  • Number of Participants With Clinical Cessation of Status Epilepticus – Adjudicated Outcomes Analysis
    • Time Frame: Within 60 minutes after the start of study drug infusion
    • Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. The Adjudicated outcomes analysis is different from Outcome measure 1 because a central clinical phenomenology core of four neurologists adjudicated from the medical records the time to seizure cessation, the time in status epilepticus before trial-drug initiation, and the cause of the seizure. For each enrollment, two neurologists from this core group conducted independent initial reviews and then determined a consensus or consulted a third adjudicator, as needed. Adjudicators were unaware of the treatment assignments and made determinations by medical record review.

Secondary Measures

  • Number of Participants With Admission to Intensive Care Unit
    • Time Frame: Admission to intensive care unit after start of study drug infusion, where the ICU is the initial inpatient unit for the patient
    • ICU admission is recorded as occurring only if the ICU is the initial inpatient unit for the patient.
  • Length of ICU Stay
    • Time Frame: number of calendar days after the day of ED arrival until hospital discharge or subject end-of-study
    • Length of stay is determined by the number of calendar days after the day of ED arrival until hospital discharge or subject end-of-study.
  • Minutes From Start of Trial Drug Infusion to Termination of Seizures for Patients With Treatment Success
    • Time Frame: start of drug infusion to seizure cessation
    • The time to termination of seizures is the interval from the start of study drug infusion to cessation of clinically apparent seizure in those who meet the primary outcome.
  • Number of Participants With Seizure Cessation Within 20 Minutes for Patients With Treatment Success
    • Time Frame: within 20 minutes
    • Number of participants with seizure cessation within 20 minutes of study drug initiation for patients with treatment success. This outcome measure was only reported in the Supplementary materials to the Primary Paper.
  • Length of Hospital Stay
    • Time Frame: length of hospital stay
    • Length of hospital stay in days

Participating in This Clinical Trial

Inclusion Criteria

Patient witnessed to seize for greater than 5 minute duration prior to treatment with study drug; Patient received adequate dose of benzodiazepines. The last dose of a benzo was administered in the 5-30 minutes prior to study drug administration. The doses may be divided.; continued or recurring seizure in the Emergency Department; Age 2 years or older Exclusion Criteria:

Known pregnancy; Prisoner; Opt-out identification; Treatment with a second line anticonvulsant (FOS, PHT, VPA, LEV, phenobarbital or other agents defined in the MoP) for this episode of SE; Treatment with sedatives with anticonvulsant properties other than benzodiazepines (propofol, etomidate, ketamine or other agents defined in the MoP); Endotracheal intubation; Acute traumatic brain injury; Known metabolic disorder; Known liver disease; Known severe renal impairment; Known allergy or other known contraindication to FOS, PHT, LEV, or VPA; Hypoglycemia < 50 mg/dL; Hyperglycemia > 400 mg/dL; Cardiac arrest and post-anoxic seizures

Gender Eligibility: All

Minimum Age: 2 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Virginia
  • Collaborator
    • University of Michigan
  • Provider of Information About this Clinical Study
    • Principal Investigator: Jaideep Kapur, MD, Professor of Neurology and Neuroscience – University of Virginia
  • Overall Official(s)
    • Jaideep Kapur, MBBS, PhD, Study Chair, University of Virginia
    • Robert Silbergleit, MD, Principal Investigator, University of Michigan
    • James Chamberlain, MD, Principal Investigator, Children’s National Health System
    • Jordan Elm, PhD, Principal Investigator, Medical University of South Carolina

References

Bleck T, Cock H, Chamberlain J, Cloyd J, Connor J, Elm J, Fountain N, Jones E, Lowenstein D, Shinnar S, Silbergleit R, Treiman D, Trinka E, Kapur J. The established status epilepticus trial 2013. Epilepsia. 2013 Sep;54 Suppl 6(0 6):89-92. doi: 10.1111/epi.12288.

Cock HR; ESETT Group. Established status epilepticus treatment trial (ESETT). Epilepsia. 2011 Oct;52 Suppl 8:50-2. doi: 10.1111/j.1528-1167.2011.03237.x.

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