Established Status Epilepticus Treatment Trial

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Benzodiazepine Refractory Status Epilepticus

Intervention / Treatment
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* Drug: Fosphenytoin
* Drug: Levetiracetam
* Drug: Valproic acid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: ESETT had 478 enrollments. They were 16 re-enrollers. This was an EFIC trial so all consents happened after treatment and all enrollments went through the same process of consent even if they were re-enrolled. Some information presented here only includes the first 400 patients since there was a prespecified stopping rule and the trial stopped early for futility.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fosphenytoin (FOS)<br>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. | Drug: Fosphenytoin<br> <br> |
| Active Comparator: Valproic acid<br>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. | Drug: Valproic acid<br> <br> |
| Active Comparator: Levetiracetam<br>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. | Drug: Levetiracetam<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Cessation of Status Epilepticus - Intention to Treat | Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. Intention to treat | Within 60 minutes after the start of study drug infusion | 
| Number of Participants With Clinical Cessation of Status Epilepticus - Per-protocol Analysis | Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. Per-protocol analysis | Within 60 minutes after the start of study drug infusion | 
| Number of Participants With Clinical Cessation of Status Epilepticus - Adjudicated Outcomes Analysis | 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. | Within 60 minutes after the start of study drug infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Admission to Intensive Care Unit | ICU admission is recorded as occurring only if the ICU is the initial inpatient unit for the patient. | Admission to intensive care unit after start of study drug infusion, where the ICU is the initial inpatient unit for the patient | 
| Length of ICU Stay | 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. | 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 | 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. | start of drug infusion to seizure cessation | 
| Number of Participants With Seizure Cessation Within 20 Minutes for Patients With Treatment Success | 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. | within 20 minutes | 
| Length of Hospital Stay | Length of hospital stay in days | length of hospital stay | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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status epilepticus, refractory, benzodiazepine, fosphenytoin, levetiracetam, valproic acid