Established Status Epilepticus Treatment Trial (ESETT)

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.

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.

Study Overview

• Status: Completed
• Conditions: Benzodiazepine Refractory Status Epilepticus
• Intervention / Treatment: Drug: Levetiracetam; Drug: Valproic acid; Drug: Fosphenytoin

• Study Type: Interventional
• Enrollment (Actual): 478
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85713
      • Banner University Medical Center - South Campus
    • Tucson, Arizona, United States, 85724
      • Banner University Medical Center-Tucson Campus
  • California
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • Sacramento, California, United States, 95817
      • UC Davis Children's Hospital
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital
    • San Francisco, California, United States, 94143
      • UCSF Medical Center
    • San Francisco, California, United States, 94145
      • UCSF Benioff Children's Hospital
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Hospital
    • Wilmington, Delaware, United States, 19803
      • A.I.DuPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20310
      • Children's National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta at Egleston
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
    • Ann Arbor, Michigan, United States, 48109
      • C.S. Mott Children's Hospital
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
    • Detroit, Michigan, United States, 48201
      • Detroit Receiving Hospital
    • Detroit, Michigan, United States, 48235
      • Sinai-Grace Hospital
  • Minnesota
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Masonic Children's Hospital
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota Medical Center
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Brooklyn, New York, United States, 11219
      • Maimonides Medical Center
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center
    • Brooklyn, New York, United States, 11203
      • Kings County Hospital Center
    • New York, New York, United States, 10032
      • NYP Columbia University Medical Center
    • New York, New York, United States, 10032
      • NYP Morgan Stanley Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Columbus, Ohio, United States, 43210
      • OSU Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University Hospital
  • Pennsylvania
    • Chester, Pennsylvania, United States, 19013
      • Crozer-Chester Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Pennsylvania Hospital
    • Philadelphia, Pennsylvania, United States, 19141
      • Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19102
      • Hahnemann University Hospital
    • Philadelphia, Pennsylvania, United States, 19125
      • Temple University Hospital Episcopal Campus
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Presbyterian Hospital
    • Pittsburgh, Pennsylvania, United States, 15219
      • UPMC Mercy Hospital
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
    • Providence, Rhode Island, United States, 02903
      • Hasbro Children's Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • Children's Medical Center UTSW
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • Houston, Texas, United States, 77030
      • Memorial Hermann Texas Medical Center
    • Houston, Texas, United States, 77026
      • Lyndon B. Johnson General Hospital
    • San Antonio, Texas, United States, 78229
      • University Health System University Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Richmond, Virginia, United States, 23298
      • VCU Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Memorial Lutheran Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Fosphenytoin
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.	Drug: Valproic acid
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.	Drug: Levetiracetam

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Safety Outcome: Life Threatening Hypotension	Life-threatening hypotension within 60 minutes of the start of study drug infusion	within 60 minutes of the start of study drug infusion
Number of Participants With Safety Outcome: Life-threatening Cardiac Arrhythmia	Life-threatening cardiac arrhythmia within 60 minutes of the start of study drug infusion	within 60 minutes of the start of study drug infusion
Number of Participants With Safety Outcome: Endotracheal Intubation	Endotracheal intubation within 60 minutes of start of study drug infusion	within 60 minutes of start of study drug infusion
Number of Participants With Safety Outcome: Acute Anaphylaxis	Acute anaphylaxis is defined as a clinical presentation consistent with life threatening allergic reaction occurring within 6 hours of the start of study drug infusions and manifested as urticaria in combination with either (1) a systolic blood pressure of < 90 mmHg sustained for greater than 5 minutes, or (2) objective evidence of airway obstruction, and for which the patient was treated with antihistamines and/or steroids.	within 6 hours of the start of study drug infusions
Number of Participants With Safety Outcome: Acute Respiratory Depression	Respiratory depression is defined as impairment of ventilation or oxygenation necessitating definitive endotracheal intubation and mechanical ventilation. It is distinct from intubations performed only for airway protection in those with decreased levels of consciousness. It does not include those getting only supraglottic airways or transient bag-valve-mask support.	24 hours
Number of Participants With Safety Outcome: Hepatic Transaminase or Ammonia Elevations	Safety outcome: Hepatic transaminase or ammonia elevations	24 hours
Number of Participants With Safety Outcome: Purple Glove Syndrome	Purple glove syndrome is defined as the presence of all three of the findings of the objective edema: discoloration, and pain in the distal extremity in which study drug was administered, with or without known extravasation, and for which there is no other evident etiology.	24 hours
Number of Participants With Safety Outcome: Death	Safety outcome: Death	30 days
Number of Participants With Safety Outcome: Acute Seizure Recurrence	acute seizure recurrence 60 minutes to 12 hours after start of study drug infusion	60 minutes to 12 hours after start of study drug infusion

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: Medical University of South Carolina; National Institute of Neurological Disorders and Stroke (NINDS); University of Michigan; University of Minnesota; Children's National Research Institute
• Investigators: Study Chair: Jaideep Kapur, MBBS, PhD, University of Virginia; Principal Investigator: James Chamberlain, MD, Children's National Health System; Principal Investigator: Jordan Elm, PhD, Medical University of South Carolina

Publications and helpful links

General Publications

• 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.
• Coralic Z, Kapur J, Olson KR, Chamberlain JM, Overbeek D, Silbergleit R. Treatment of Toxin-Related Status Epilepticus With Levetiracetam, Fosphenytoin, or Valproate in Patients Enrolled in the Established Status Epilepticus Treatment Trial. Ann Emerg Med. 2022 Sep;80(3):194-202. doi: 10.1016/j.annemergmed.2022.04.020. Epub 2022 Jun 17.
• Rosenthal ES, Elm JJ, Ingles J, Rogers AJ, Terndrup TE, Holsti M, Thomas DG, Babcock L, Okada PJ, Lipsky RH, Miller JB, Hickey RW, Barra ME, Bleck TP, Cloyd JC, Silbergleit R, Lowenstein DH, Coles LD, Kapur J, Shinnar S, Chamberlain JM; Established Status Epilepticus Treatment Trial Study Group. Early Neurologic Recovery, Practice Pattern Variation, and the Risk of Endotracheal Intubation Following Established Status Epilepticus. Neurology. 2021 May 11;96(19):e2372-e2386. doi: 10.1212/WNL.0000000000011879. Epub 2021 Mar 23.
• Sathe AG, Brundage RC, Ivaturi V, Cloyd JC, Chamberlain JM, Elm JJ, Silbergleit R, Kapur J, Coles LD. A pharmacokinetic simulation study to assess the performance of a sparse blood sampling approach to quantify early drug exposure. Clin Transl Sci. 2021 Jul;14(4):1444-1451. doi: 10.1111/cts.13004. Epub 2021 May 1.
• Sathe AG, Underwood E, Coles LD, Elm JJ, Silbergleit R, Chamberlain JM, Kapur J, Cock HR, Fountain NB, Shinnar S, Lowenstein DH, Rosenthal ES, Conwit RA, Bleck TP, Cloyd JC. Patterns of benzodiazepine underdosing in the Established Status Epilepticus Treatment Trial. Epilepsia. 2021 Mar;62(3):795-806. doi: 10.1111/epi.16825. Epub 2021 Feb 10.
• Sathe AG, Mishra U, Ivaturi V, Brundage RC, Cloyd JC, Elm JJ, Chamberlain JM, Silbergleit R, Kapur J, Lowenstein DH, Shinnar S, Cock HR, Fountain NB, Babcock L, Coles LD. Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High-Dose Intravenous Administration in Young Children With Benzodiazepine-Refractory Status Epilepticus. J Clin Pharmacol. 2021 Jun;61(6):763-768. doi: 10.1002/jcph.1801. Epub 2021 Jan 12.
• Scicluna VM, Biros M, Harney DK, Jones EB, Mitchell AR, Pentz RD, Silbergleit R, Speight CD, Wright DW, Dickert NW. Patient and Surrogate Postenrollment Perspectives on Research Using the Exception From Informed Consent: An Integrated Survey. Ann Emerg Med. 2020 Sep;76(3):343-349. doi: 10.1016/j.annemergmed.2020.03.017. Epub 2020 May 21.
• Chamberlain JM, Kapur J, Shinnar S, Elm J, Holsti M, Babcock L, Rogers A, Barsan W, Cloyd J, Lowenstein D, Bleck TP, Conwit R, Meinzer C, Cock H, Fountain NB, Underwood E, Connor JT, Silbergleit R; Neurological Emergencies Treatment Trials; Pediatric Emergency Care Applied Research Network investigators. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. Lancet. 2020 Apr 11;395(10231):1217-1224. doi: 10.1016/S0140-6736(20)30611-5. Epub 2020 Mar 20.
• Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor JT, Silbergleit R; NETT and PECARN Investigators. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019 Nov 28;381(22):2103-2113. doi: 10.1056/NEJMoa1905795.
• Sathe AG, Tillman H, Coles LD, Elm JJ, Silbergleit R, Chamberlain J, Kapur J, Cock HR, Fountain NB, Shinnar S, Lowenstein DH, Conwit RA, Bleck TP, Cloyd JC. Underdosing of Benzodiazepines in Patients With Status Epilepticus Enrolled in Established Status Epilepticus Treatment Trial. Acad Emerg Med. 2019 Aug;26(8):940-943. doi: 10.1111/acem.13811. Epub 2019 Jul 18. No abstract available.

Helpful Links

• ESETT Website

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (ACTUAL): February 1, 2019
• Study Completion (ACTUAL): May 1, 2019

Study Registration Dates

• First Submitted: October 8, 2013
• First Submitted That Met QC Criteria: October 8, 2013
• First Posted (ESTIMATE): October 10, 2013

Study Record Updates

• Last Update Posted (ACTUAL): June 14, 2021
• Last Update Submitted That Met QC Criteria: May 19, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: status epilepticus, refractory, benzodiazepine, fosphenytoin, levetiracetam, valproic acid
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Status Epilepticus; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; GABA Agents; Anticonvulsants; Sodium Channel Blockers; Antimanic Agents; Nootropic Agents; Valproic Acid; Levetiracetam; Fosphenytoin
• Other Study ID Numbers: 18078; 119756 (OTHER: ClinicalTrials.gov); U01NS088034 (NIH)