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Established Status Epilepticus Treatment Trial (ESETT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01960075
Recruitment Status : Completed
First Posted : October 10, 2013
Results First Posted : February 28, 2020
Last Update Posted : February 28, 2020
Sponsor:
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

Tracking Information
First Submitted Date  ICMJE October 8, 2013
First Posted Date  ICMJE October 10, 2013
Results First Submitted Date  ICMJE December 30, 2019
Results First Posted Date  ICMJE February 28, 2020
Last Update Posted Date February 28, 2020
Study Start Date  ICMJE October 2015
Actual Primary Completion Date February 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 14, 2020)
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 8, 2013)
Clinical cessation of SE without life threatening hypotension or cardiac arrhythmias. [ Time Frame: 60 minutes from enrollment ]
The primary outcome is clinical cessation of status epilepticus, without recurrent seizures, life-threatening hypotension or cardiac arrhythmia, or use of additional anti-seizure medications within 60 minutes of the start of study drug infusion.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2020)
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: October 8, 2013)
Admission to ICU, intubation and mortality [ Time Frame: 7 days from enrollment ]
Secondary objective is to measure the impact of the three drugs on secondary outcomes: time to termination of clinical seizures, intubation or admission to ICU within 24 hrs. of enrollment, mortality and clinical cessation of status epileptcis and adverse effects analyzed separately.
Current Other Pre-specified Outcome Measures
 (submitted: February 14, 2020)
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • Number of Participants With Safety Outcome: Hepatic Transaminase or Ammonia Elevations [ Time Frame: 24 hours ]
    Safety outcome: Hepatic transaminase or ammonia elevations
  • 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.
  • Number of Participants With Safety Outcome: Death [ Time Frame: 30 days ]
    Safety outcome: Death
  • 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
Original Other Pre-specified Outcome Measures
 (submitted: October 8, 2013)
Effectiveness in children [ Time Frame: 60 minutes ]
Final objective is to determine the effectiveness, rate of adverse reactions of these drugs in children with established status epilepticus.
 
Descriptive Information
Brief Title  ICMJE Established Status Epilepticus Treatment Trial
Official Title  ICMJE 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.
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE Benzodiazepine Refractory Status Epilepticus
Intervention  ICMJE
  • Drug: Fosphenytoin
  • Drug: Levetiracetam
  • Drug: Valproic acid
Study Arms  ICMJE
  • 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.
    Intervention: 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.
    Intervention: 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.
    Intervention: Drug: Levetiracetam
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 15, 2019)
478
Original Estimated Enrollment  ICMJE
 (submitted: October 8, 2013)
795
Actual Study Completion Date  ICMJE May 2019
Actual Primary Completion Date February 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01960075
Other Study ID Numbers  ICMJE 18078
119756 ( Other Identifier: ClinicalTrials.gov )
U01NS088034 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jaideep Kapur, MD, University of Virginia
Study Sponsor  ICMJE University of Virginia
Collaborators  ICMJE
  • 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  ICMJE
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
PRS Account University of Virginia
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP