Established Status Epilepticus Treatment Trial (ESETT)

• ClinicalTrials.gov Identifier: NCT01960075
• Recruitment Status: Completed
• First Posted: October 10, 2013
• Results First Posted: February 28, 2020
• Last Update Posted: June 14, 2021
• Sponsor: University of Virginia
• Collaborators: University of Michigan; Medical University of South Carolina; Children's National Research Institute; University of Minnesota; National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Jaideep Kapur, MD, University of Virginia

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Benzodiazepine Refractory Status Epilepticus	Drug: Fosphenytoin; Drug: Levetiracetam; Drug: Valproic acid	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 478 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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 (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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 Start Date: October 2015
• Actual Primary Completion Date: February 2019
• Actual Study Completion Date: May 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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
2. 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
3. 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 Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. Length of Hospital Stay [ Time Frame: length of hospital stay ]
   Length of hospital stay in days

Other Outcome Measures:

1. Number of Participants With Safety Outcome: Life Threatening Hypotension [ Time Frame: within 60 minutes of the start of study drug infusion ]
   Life-threatening hypotension within 60 minutes of the start of study drug infusion
2. Number of Participants With Safety Outcome: Life-threatening Cardiac Arrhythmia [ Time Frame: within 60 minutes of the start of study drug infusion ]
   Life-threatening cardiac arrhythmia within 60 minutes of the start of study drug infusion
3. Number of Participants With Safety Outcome: Endotracheal Intubation [ Time Frame: within 60 minutes of start of study drug infusion ]
   Endotracheal intubation within 60 minutes of start of study drug infusion
4. Number of Participants With Safety Outcome: Acute Anaphylaxis [ Time Frame: within 6 hours of the start of study drug infusions ]
   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.
5. Number of Participants With Safety Outcome: Acute Respiratory Depression [ Time Frame: 24 hours ]
   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.
6. Number of Participants With Safety Outcome: Hepatic Transaminase or Ammonia Elevations [ Time Frame: 24 hours ]
   Safety outcome: Hepatic transaminase or ammonia elevations
7. Number of Participants With Safety Outcome: Purple Glove Syndrome [ Time Frame: 24 hours ]
   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.
8. Number of Participants With Safety Outcome: Death [ Time Frame: 30 days ]
   Safety outcome: Death
9. Number of Participants With Safety Outcome: Acute Seizure Recurrence [ Time Frame: 60 minutes to 12 hours after start of study drug infusion ]
   acute seizure recurrence 60 minutes to 12 hours after start of study drug infusion

Eligibility Criteria

• Ages Eligible for Study: 2 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Banner University Medical Center - South Campus

Tucson, Arizona, United States, 85713

Banner University Medical Center-Tucson Campus

Tucson, Arizona, United States, 85724

United States, California

Ronald Reagan UCLA Medical Center

Los Angeles, California, United States, 90095

UC Davis Children's Hospital

Sacramento, California, United States, 95817

San Francisco General Hospital

San Francisco, California, United States, 94110

UCSF Medical Center

San Francisco, California, United States, 94143

UCSF Benioff Children's Hospital

San Francisco, California, United States, 94145

Stanford University Medical Center

Stanford, California, United States, 94305

United States, Delaware

Christiana Hospital

Newark, Delaware, United States, 19718

A.I.DuPont Hospital for Children

Wilmington, Delaware, United States, 19803

United States, District of Columbia

Children's National Medical Center

Washington, District of Columbia, United States, 20310

United States, Georgia

Grady Memorial Hospital

Atlanta, Georgia, United States, 30303

Children's Healthcare of Atlanta at Egleston

Atlanta, Georgia, United States, 30322

United States, Kentucky

University of Kentucky Hospital

Lexington, Kentucky, United States, 40536

United States, Maryland

University of maryland Medical Center

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Michigan

C.S. Mott Children's Hospital

Ann Arbor, Michigan, United States, 48109

University of Michigan Medical Center

Ann Arbor, Michigan, United States, 48109

Children's Hospital of Michigan

Detroit, Michigan, United States, 48201

Detroit Receiving Hospital

Detroit, Michigan, United States, 48201

Henry Ford Hospital

Detroit, Michigan, United States, 48202

Sinai-Grace Hospital

Detroit, Michigan, United States, 48235

United States, Minnesota

Fairview Southdale Hospital

Edina, Minnesota, United States, 55435

Hennepin County Medical Center

Minneapolis, Minnesota, United States, 55415

University of Minnesota Medical Center

Minneapolis, Minnesota, United States, 55454

University of Minnesota Masonic Children's Hospital

Minneapolis, Minnesota, United States, 55455

Regions Hospital

Saint Paul, Minnesota, United States, 55101

United States, Missouri

St. Louis Children's Hospital

Saint Louis, Missouri, United States, 63110

United States, New Jersey

Hackensack University Medical Center

Hackensack, New Jersey, United States, 07601

United States, New York

Kings County Hospital Center

Brooklyn, New York, United States, 11203

SUNY Downstate Medical Center

Brooklyn, New York, United States, 11203

Maimonides Medical Center

Brooklyn, New York, United States, 11219

NYP Columbia University Medical Center

New York, New York, United States, 10032

NYP Morgan Stanley Children's Hospital

New York, New York, United States, 10032

United States, Ohio

University of Cincinnati Medical Center

Cincinnati, Ohio, United States, 45219

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

OSU Wexner Medical Center

Columbus, Ohio, United States, 43210

United States, Oregon

Oregon Health & Science University Hospital

Portland, Oregon, United States, 97239

United States, Pennsylvania

Crozer-Chester Medical Center

Chester, Pennsylvania, United States, 19013

Penn State Hershey Medical Center

Hershey, Pennsylvania, United States, 17033

Hahnemann University Hospital

Philadelphia, Pennsylvania, United States, 19102

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Penn Presbyterian Medical Center

Philadelphia, Pennsylvania, United States, 19104

Pennsylvania Hospital

Philadelphia, Pennsylvania, United States, 19107

Temple University Hospital Episcopal Campus

Philadelphia, Pennsylvania, United States, 19125

Temple University Hospital

Philadelphia, Pennsylvania, United States, 19140

Einstein Medical Center

Philadelphia, Pennsylvania, United States, 19141

Allegheny General Hospital

Pittsburgh, Pennsylvania, United States, 15212

UPMC Presbyterian Hospital

Pittsburgh, Pennsylvania, United States, 15213

UPMC Mercy Hospital

Pittsburgh, Pennsylvania, United States, 15219

Children's Hospital of Pittsburgh UPMC

Pittsburgh, Pennsylvania, United States, 15224

United States, Rhode Island

Hasbro Children's Hospital

Providence, Rhode Island, United States, 02903

Rhode Island Hospital

Providence, Rhode Island, United States, 02903

United States, Texas

Children's Medical Center UTSW

Dallas, Texas, United States, 75390

Lyndon B. Johnson General Hospital

Houston, Texas, United States, 77026

Memorial Hermann Texas medical Center

Houston, Texas, United States, 77030

Texas Children's Hospital

Houston, Texas, United States, 77030

University Health System University Hospital

San Antonio, Texas, United States, 78229

United States, Utah

Primary Children's Hospital

Salt Lake City, Utah, United States, 84113

United States, Virginia

University of Virginia

Charlottesville, Virginia, United States, 22908

VCU Medical Center

Richmond, Virginia, United States, 23298

United States, Wisconsin

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Froedtert Memorial Lutheran Hospital

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

University of Virginia

University of Michigan

Medical University of South Carolina

Children's National Research Institute

University of Minnesota

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Study Chair: Jaideep Kapur, MBBS, PhD; University of Virginia
• Principal Investigator: Robert Silbergleit, MD; University of Michigan
• Principal Investigator: James Chamberlain, MD; Children's National Health System
• Principal Investigator: Jordan Elm, PhD; Medical University of South Carolina

  Study Documents (Full-Text)

Documents provided by Jaideep Kapur, MD, University of Virginia:

Study Protocol and Statistical Analysis Plan  [PDF] December 5, 2016

Informed Consent Form  [PDF] January 5, 2015

More Information

Additional Information:

ESETT Website 

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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. Erratum In: Lancet. 2023 May 6;401(10387):1498.

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.

• Responsible Party: Jaideep Kapur, MD, Professor of Neurology and Neuroscience, University of Virginia
• ClinicalTrials.gov Identifier: NCT01960075
• Other Study ID Numbers: 18078; 119756 ( Other Identifier: ClinicalTrials.gov ); U01NS088034 ( U.S. NIH Grant/Contract )
• First Posted: October 10, 2013
• Results First Posted: February 28, 2020
• Last Update Posted: June 14, 2021
• Last Verified: May 2021

Keywords provided by Jaideep Kapur, MD, University of Virginia:

status epilepticus, refractory, benzodiazepine, fosphenytoin, levetiracetam, valproic acid

Additional relevant MeSH terms:

Fosphenytoin; Status Epilepticus; Seizures; Neurologic Manifestations; Nervous System Diseases; Levetiracetam; Valproic Acid; Anticonvulsants; Nootropic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; GABA Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Antimanic Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Sodium Channel Blockers; Membrane Transport Modulators