Clinical trial NCT01960075: Established Status Epilepticus Treatment Trial
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Benzodiazepine Refractory Status Epilepticus
Keywords: status epilepticus, refractory, benzodiazepine, fosphenytoin, levetiracetam, valproic acid
Lead sponsor: University of Virginia
Sponsor class: OTHER
Collaborators: name: University of Michigan
name: Medical University of South Carolina
name: Children's National Research Institute
name: University of Minnesota
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2013-10-10
Enrollment: 478
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Number of Participants With Clinical Cessation of Status Epilepticus - Intention to Treat
timeFrame: Within 60 minutes after the start of study drug infusion
measure: Number of Participants With Clinical Cessation of Status Epilepticus - Per-protocol Analysis
timeFrame: Within 60 minutes after the start of study drug infusion
measure: Number of Participants With Clinical Cessation of Status Epilepticus - Adjudicated Outcomes Analysis
timeFrame: Within 60 minutes after the start of study drug infusion
Secondary outcomes:
measure: Number of Participants With Admission to Intensive Care Unit
timeFrame: Admission to intensive care unit after start of study drug infusion, where the ICU is the initial inpatient unit for the patient
measure: Length of ICU Stay
timeFrame: number of calendar days after the day of ED arrival until hospital discharge or subject end-of-study
measure: Minutes From Start of Trial Drug Infusion to Termination of Seizures for Patients With Treatment Success
timeFrame: start of drug infusion to seizure cessation
measure: Number of Participants With Seizure Cessation Within 20 Minutes for Patients With Treatment Success
timeFrame: within 20 minutes
measure: Length of Hospital Stay
timeFrame: length of hospital stay
Other outcomes:
measure: Number of Participants With Safety Outcome: Life Threatening Hypotension
timeFrame: within 60 minutes of the start of study drug infusion
measure: Number of Participants With Safety Outcome: Life-threatening Cardiac Arrhythmia
timeFrame: within 60 minutes of the start of study drug infusion
measure: Number of Participants With Safety Outcome: Endotracheal Intubation
timeFrame: within 60 minutes of start of study drug infusion
measure: Number of Participants With Safety Outcome: Acute Anaphylaxis
timeFrame: within 6 hours of the start of study drug infusions
measure: Number of Participants With Safety Outcome: Acute Respiratory Depression
timeFrame: 24 hours
measure: Number of Participants With Safety Outcome: Hepatic Transaminase or Ammonia Elevations
timeFrame: 24 hours
measure: Number of Participants With Safety Outcome: Purple Glove Syndrome
timeFrame: 24 hours
measure: Number of Participants With Safety Outcome: Death
timeFrame: 30 days
measure: Number of Participants With Safety Outcome: Acute Seizure Recurrence
timeFrame: 60 minutes to 12 hours after start of study drug infusion
Locations:
city: Tucson
country: United States
facility: Banner University Medical Center - South Campus
state: Arizona
city: Tucson
country: United States
facility: Banner University Medical Center-Tucson Campus
state: Arizona
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis Children's Hospital
state: California
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Newark
country: United States
facility: Christiana Hospital
state: Delaware
city: Wilmington
country: United States
facility: A.I.DuPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta at Egleston
state: Georgia
city: Lexington
country: United States
facility: University of Kentucky Hospital
state: Kentucky
city: Baltimore
country: United States
facility: University of maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: C.S. Mott Children's Hospital
state: Michigan
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Detroit
country: United States
facility: Detroit Receiving Hospital
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Detroit
country: United States
facility: Sinai-Grace Hospital
state: Michigan
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Masonic Children's Hospital
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Brooklyn
country: United States
facility: Kings County Hospital Center
state: New York
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center
state: New York
city: Brooklyn
country: United States
facility: Maimonides Medical Center
state: New York
city: New York
country: United States
facility: NYP Columbia University Medical Center
state: New York
city: New York
country: United States
facility: NYP Morgan Stanley Children's Hospital
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: OSU Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University Hospital
state: Oregon
city: Chester
country: United States
facility: Crozer-Chester Medical Center
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hahnemann University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Penn Presbyterian Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pennsylvania Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital Episcopal Campus
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Einstein Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Mercy Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh UPMC
state: Pennsylvania
city: Providence
country: United States
facility: Hasbro Children's Hospital
state: Rhode Island
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Dallas
country: United States
facility: Children's Medical Center UTSW
state: Texas
city: Houston
country: United States
facility: Lyndon B. Johnson General Hospital
state: Texas
city: Houston
country: United States
facility: Memorial Hermann Texas medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: San Antonio
country: United States
facility: University Health System University Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Richmond
country: United States
facility: VCU Medical Center
state: Virginia
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert Memorial Lutheran Hospital
state: Wisconsin
Study officials:
affiliation: University of Virginia
name: Jaideep Kapur, MBBS, PhD
role: STUDY_CHAIR
affiliation: University of Michigan
name: Robert Silbergleit, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's National Health System
name: James Chamberlain, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of South Carolina
name: Jordan Elm, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.