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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 : June 14, 2021
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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Benzodiazepine Refractory Status Epilepticus
Interventions Drug: Fosphenytoin
Drug: Levetiracetam
Drug: Valproic acid
Enrollment 478
Recruitment Details ESETT had a total of 478 enrollments. This number includes 16 re-enrollers. This was an EFIC trial so all consents happened after treatment. All enrollments went through the same process of consent even if they were reenrolled. The first 400 patients were used in several parts of analyses since the trial stopped early for futility (prespecified).
Pre-assignment Details  
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Period Title: Overall Study
Started 149 149 180
Completed 141 146 173
Not Completed 8 3 7
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam Total
Hide Arm/Group Description

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Total of all reporting groups
Overall Number of Baseline Participants 118 121 145 384
Hide Baseline Analysis Population Description
The difference from Participant Flow is because the total of 384 is from the first 400 patients and excludes 16 re-enrollers in the study, and the first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 118 participants 121 participants 145 participants 384 participants
32.8  (25.4) 32.2  (25.4) 33.3  (26.0) 32.8  (25.6)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Age Number Analyzed 118 participants 121 participants 145 participants 384 participants
0 - 5 yr
24
  20.3%
28
  23.1%
30
  20.7%
82
  21.4%
6 - 10 yr
15
  12.7%
7
   5.8%
17
  11.7%
39
  10.2%
11 - 20 yr
10
   8.5%
18
  14.9%
9
   6.2%
37
   9.6%
21 - 40 yr
20
  16.9%
19
  15.7%
31
  21.4%
70
  18.2%
41 - 60 yr
26
  22.0%
26
  21.5%
34
  23.4%
86
  22.4%
=> 61 yr
23
  19.5%
23
  19.0%
24
  16.6%
70
  18.2%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 118 participants 121 participants 145 participants 384 participants
Female
47
  39.8%
56
  46.3%
68
  46.9%
171
  44.5%
Male
71
  60.2%
65
  53.7%
77
  53.1%
213
  55.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race/Ethnicity Number Analyzed 118 participants 121 participants 145 participants 384 participants
Black
49
  41.5%
54
  44.6%
62
  42.8%
165
  43.0%
White
49
  41.5%
49
  40.5%
62
  42.8%
160
  41.7%
Other, >1 race, or unknown
20
  16.9%
18
  14.9%
21
  14.5%
59
  15.4%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Hispanic Ethnicity Number Analyzed 118 participants 121 participants 145 participants 384 participants
18
  15.3%
22
  18.2%
23
  15.9%
63
  16.4%
Prior history of epilepsy  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 118 participants 121 participants 145 participants 384 participants
80
  67.8%
83
  68.6%
97
  66.9%
260
  67.7%
Final Diagnosis  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 118 participants 121 participants 145 participants 384 participants
Seizure/Status Epilepticus
104
  88.1%
102
  84.3%
128
  88.3%
334
  87.0%
Non-epileptic spell
11
   9.3%
13
  10.7%
13
   9.0%
37
   9.6%
Unable to adjudicate
3
   2.5%
6
   5.0%
4
   2.8%
13
   3.4%
1.Primary Outcome
Title Number of Participants With Clinical Cessation of Status Epilepticus - Intention to Treat
Hide Description Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. Intention to treat
Time Frame Within 60 minutes after the start of study drug infusion
Hide Outcome Measure Data
Hide Analysis Population Description
The difference from Participant Flow is because the total of 384 is from the first 400 patients and excludes 16 re-enrollers in the study. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 118 121 145
Measure Type: Count of Participants
Unit of Measure: Participants
53
  44.9%
56
  46.3%
68
  46.9%
2.Primary Outcome
Title Number of Participants With Clinical Cessation of Status Epilepticus - Per-protocol Analysis
Hide Description Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. Per-protocol analysis
Time Frame Within 60 minutes after the start of study drug infusion
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population for this outcome is the Per-protocol population, which is all patients who completed the study without major protocol deviations.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 79 91 109
Measure Type: Count of Participants
Unit of Measure: Participants
37
  46.8%
43
  47.3%
51
  46.8%
3.Primary Outcome
Title Number of Participants With Clinical Cessation of Status Epilepticus - Adjudicated Outcomes Analysis
Hide Description 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.
Time Frame Within 60 minutes after the start of study drug infusion
Hide Outcome Measure Data
Hide Analysis Population Description
The difference from Participant Flow is because the total of 384 is from the first 400 patients and excludes 16 re-enrollers in the study. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 118 121 145
Measure Type: Count of Participants
Unit of Measure: Participants
57
  48.3%
60
  49.6%
67
  46.2%
4.Secondary Outcome
Title Number of Participants With Admission to Intensive Care Unit
Hide Description ICU admission is recorded as occurring only if the ICU is the initial inpatient unit for the patient.
Time Frame Admission to intensive care unit after start of study drug infusion, where the ICU is the initial inpatient unit for the patient
Hide Outcome Measure Data
Hide Analysis Population Description
The difference from Participant Flow is because the total of 384 is from the first 400 patients and excludes 16 re-enrollers in the study. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 118 121 145
Measure Type: Count of Participants
Unit of Measure: Participants
70
  59.3%
71
  58.7%
87
  60.0%
5.Secondary Outcome
Title Length of ICU Stay
Hide Description 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.
Time Frame number of calendar days after the day of ED arrival until hospital discharge or subject end-of-study
Hide Outcome Measure Data
Hide Analysis Population Description
The difference from Participant Flow is because the total of 384 is from the first 400 patients and excludes 16 re-enrollers in the study. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 118 121 145
Median (Inter-Quartile Range)
Unit of Measure: days
1
(0 to 3)
1
(0 to 3)
1
(0 to 3)
6.Secondary Outcome
Title Minutes From Start of Trial Drug Infusion to Termination of Seizures for Patients With Treatment Success
Hide Description 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.
Time Frame start of drug infusion to seizure cessation
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population here is different than Participant Flow because it includes only the patients who had this data available. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 15 10 14
Median (Inter-Quartile Range)
Unit of Measure: minutes
11.7
(7.5 to 20.9)
7.0
(4.6 to 14.9)
10.5
(5.7 to 15.5)
7.Secondary Outcome
Title Number of Participants With Seizure Cessation Within 20 Minutes for Patients With Treatment Success
Hide Description 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.
Time Frame within 20 minutes
Hide Outcome Measure Data
Hide Analysis Population Description
The population is different than Participant flow because it is only those with treatment success. This outcome measure was only reported in the Supplementary materials to the Primary Paper.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 53 55 68
Measure Type: Count of Participants
Unit of Measure: Participants
43
  81.1%
43
  78.2%
53
  77.9%
8.Secondary Outcome
Title Length of Hospital Stay
Hide Description Length of hospital stay in days
Time Frame length of hospital stay
Hide Outcome Measure Data
Hide Analysis Population Description
The difference from Participant Flow is because the total of 384 is from the first 400 patients and excludes 16 re-enrollers in the study. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 118 121 145
Median (Inter-Quartile Range)
Unit of Measure: days
3
(1 to 6)
3
(2 to 6)
3
(1 to 7)
9.Other Pre-specified Outcome
Title Number of Participants With Safety Outcome: Life Threatening Hypotension
Hide Description Life-threatening hypotension within 60 minutes of the start of study drug infusion
Time Frame within 60 minutes of the start of study drug infusion
Hide Outcome Measure Data
Hide Analysis Population Description
The first 400 patients were analyzed for this outcome. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 125 125 150
Measure Type: Count of Participants
Unit of Measure: Participants
4
   3.2%
2
   1.6%
1
   0.7%
10.Other Pre-specified Outcome
Title Number of Participants With Safety Outcome: Life-threatening Cardiac Arrhythmia
Hide Description Life-threatening cardiac arrhythmia within 60 minutes of the start of study drug infusion
Time Frame within 60 minutes of the start of study drug infusion
Hide Outcome Measure Data
Hide Analysis Population Description
The first 400 patients were analyzed for this outcome. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 125 125 150
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
1
   0.7%
11.Other Pre-specified Outcome
Title Number of Participants With Safety Outcome: Endotracheal Intubation
Hide Description Endotracheal intubation within 60 minutes of start of study drug infusion
Time Frame within 60 minutes of start of study drug infusion
Hide Outcome Measure Data
Hide Analysis Population Description
The first 400 patients were analyzed for this outcome. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 125 125 150
Measure Type: Count of Participants
Unit of Measure: Participants
33
  26.4%
21
  16.8%
30
  20.0%
12.Other Pre-specified Outcome
Title Number of Participants With Safety Outcome: Acute Anaphylaxis
Hide Description 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.
Time Frame within 6 hours of the start of study drug infusions
Hide Outcome Measure Data
Hide Analysis Population Description
The first 400 patients were analyzed for this outcome. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 125 125 150
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
0
   0.0%
13.Other Pre-specified Outcome
Title Number of Participants With Safety Outcome: Acute Respiratory Depression
Hide Description 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.
Time Frame 24 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The first 400 patients were analyzed for this outcome. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 125 125 150
Measure Type: Count of Participants
Unit of Measure: Participants
16
  12.8%
10
   8.0%
12
   8.0%
14.Other Pre-specified Outcome
Title Number of Participants With Safety Outcome: Hepatic Transaminase or Ammonia Elevations
Hide Description Safety outcome: Hepatic transaminase or ammonia elevations
Time Frame 24 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The first 400 patients were analyzed for this outcome. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 125 125 150
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
1
   0.8%
1
   0.7%
15.Other Pre-specified Outcome
Title Number of Participants With Safety Outcome: Purple Glove Syndrome
Hide Description 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.
Time Frame 24 hours
Hide Outcome Measure Data
Hide Analysis Population Description
The first 400 patients were analyzed for this outcome. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 125 125 150
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
0
   0.0%
16.Other Pre-specified Outcome
Title Number of Participants With Safety Outcome: Death
Hide Description Safety outcome: Death
Time Frame 30 days
Hide Outcome Measure Data
Hide Analysis Population Description
The first 400 patients were analyzed for this outcome. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 125 125 150
Measure Type: Count of Participants
Unit of Measure: Participants
3
   2.4%
2
   1.6%
7
   4.7%
17.Other Pre-specified Outcome
Title Number of Participants With Safety Outcome: Acute Seizure Recurrence
Hide Description acute seizure recurrence 60 minutes to 12 hours after start of study drug infusion
Time Frame 60 minutes to 12 hours after start of study drug infusion
Hide Outcome Measure Data
Hide Analysis Population Description
The first 400 patients were analyzed for this outcome. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description:

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

Overall Number of Participants Analyzed 125 125 150
Measure Type: Count of Participants
Unit of Measure: Participants
14
  11.2%
14
  11.2%
16
  10.7%
Time Frame Data on adverse events were collected through the first 24 hours after enrollment, for the duration of the trial.
Adverse Event Reporting Description All-Cause mortality data was collected for the first 400 subjects, which is why the numbers in the All-cause mortality section differ from Participant flow. The first 400 patients were used because of the prespecified stopping rule and the trial stopped for futility.
 
Arm/Group Title Fosphenytoin (FOS) Valproic Acid Levetiracetam
Hide Arm/Group Description

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.

Fosphenytoin

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.

Valproic acid

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.

Levetiracetam

All-Cause Mortality
Fosphenytoin (FOS) Valproic Acid Levetiracetam
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/125 (2.40%)      2/125 (1.60%)      7/150 (4.67%)    
Hide Serious Adverse Events
Fosphenytoin (FOS) Valproic Acid Levetiracetam
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   57/125 (45.60%)      46/125 (36.80%)      64/150 (42.67%)    
Cardiac disorders       
Atrial fibrillation *  1/125 (0.80%)  1 1/125 (0.80%)  1 0/150 (0.00%)  0
Cardiac arrest *  1/125 (0.80%)  1 0/125 (0.00%)  0 2/150 (1.33%)  2
Intracardiac thrombus *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Supraventricular tachycardia *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Gastrointestinal disorders       
Dysphagia *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Gastrointestinal haemorrhage *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Intestinal ischaemia *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Retroperitoneal haemorrhage *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Small intestinal obstruction *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
General disorders       
Device malfunction *  0/125 (0.00%)  0 2/125 (1.60%)  2 0/150 (0.00%)  0
Hypothermia *  0/125 (0.00%)  0 2/125 (1.60%)  2 0/150 (0.00%)  0
Infusion site extravasation *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Hepatobiliary disorders       
Hepatic failure *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Infections and infestations       
Bacteraemia *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Clostridium difficile colitis *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Endocarditis *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Pneumonia *  2/125 (1.60%)  2 2/125 (1.60%)  2 4/150 (2.67%)  4
Respiratory tract infection *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Sepsis *  2/125 (1.60%)  2 2/125 (1.60%)  2 1/150 (0.67%)  1
Septic shock *  0/125 (0.00%)  0 1/125 (0.80%)  1 1/150 (0.67%)  1
Injury, poisoning and procedural complications       
Accidental overdose *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Investigations       
Liver function test abnormal *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Metabolism and nutrition disorders       
Hypoglycaemia *  0/125 (0.00%)  0 1/125 (0.80%)  1 1/150 (0.67%)  1
Hypokalaemia *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Musculoskeletal and connective tissue disorders       
Muscle haemorrhage *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Rhabdomyolysis *  0/125 (0.00%)  0 0/125 (0.00%)  0 3/150 (2.00%)  3
Nervous system disorders       
Cerebral infarction *  2/125 (1.60%)  2 1/125 (0.80%)  1 0/150 (0.00%)  0
Cerebrovascular accident *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Cerebrovascular spasm *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Convulsion *  25/125 (20.00%)  26 23/125 (18.40%)  23 30/150 (20.00%)  32
Depressed level of consciousness *  12/125 (9.60%)  12 9/125 (7.20%)  9 15/150 (10.00%)  15
Encephalopathy *  0/125 (0.00%)  0 1/125 (0.80%)  1 4/150 (2.67%)  4
Haemorrhage intracranial *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Hypoxic-ischaemic encephalopathy *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Psychiatric disorders       
Agitation *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Conversion disorder *  1/125 (0.80%)  1 0/125 (0.00%)  0 2/150 (1.33%)  2
Delirium *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Renal and urinary disorders       
Urinary retention *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Aspiration *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Epistaxis *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Hypoxia *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Obstructive airways disorder *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Pleural effusion *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Respiratory depression *  15/125 (12.00%)  16 8/125 (6.40%)  8 10/150 (6.67%)  10
Respiratory failure *  2/125 (1.60%)  2 4/125 (3.20%)  4 1/150 (0.67%)  1
Stridor *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Vascular disorders       
Deep vein thrombosis *  0/125 (0.00%)  0 2/125 (1.60%)  2 1/150 (0.67%)  1
Hypotension *  7/125 (5.60%)  7 6/125 (4.80%)  6 4/150 (2.67%)  4
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Fosphenytoin (FOS) Valproic Acid Levetiracetam
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   28/125 (22.40%)      22/125 (17.60%)      25/150 (16.67%)    
Blood and lymphatic system disorders       
Leukocytosis *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Cardiac disorders       
Arrhythmia *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Tachycardia *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Nausea *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Pancreatitis *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Vomiting *  1/125 (0.80%)  1 2/125 (1.60%)  2 2/150 (1.33%)  2
General disorders       
Hyperthermia *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Infusion site extravasation *  1/125 (0.80%)  1 0/125 (0.00%)  0 1/150 (0.67%)  1
Pyrexia *  2/125 (1.60%)  2 1/125 (0.80%)  1 3/150 (2.00%)  3
Systemic inflammatory response syndrome *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Immune system disorders       
Hypersensitivity *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Injury, poisoning and procedural complications       
Fall *  2/125 (1.60%)  2 0/125 (0.00%)  0 0/150 (0.00%)  0
Investigations       
Heart rate decreased *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Troponin increased *  0/125 (0.00%)  0 1/125 (0.80%)  1 2/150 (1.33%)  2
Metabolism and nutrition disorders       
Hypernatraemia *  0/125 (0.00%)  0 1/125 (0.80%)  1 1/150 (0.67%)  1
Hyperphosphataemia *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Hypocalcaemia *  0/125 (0.00%)  0 2/125 (1.60%)  2 3/150 (2.00%)  3
Hypoglycaemia *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Hypokalaemia *  0/125 (0.00%)  0 1/125 (0.80%)  1 1/150 (0.67%)  1
Hypomagnesaemia *  0/125 (0.00%)  0 2/125 (1.60%)  2 0/150 (0.00%)  0
Hypophosphataemia *  0/125 (0.00%)  0 3/125 (2.40%)  3 1/150 (0.67%)  1
Musculoskeletal and connective tissue disorders       
Neck pain *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Rhabdomyolysis *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Nervous system disorders       
Balance disorder *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Convulsion *  3/125 (2.40%)  3 8/125 (6.40%)  8 4/150 (2.67%)  4
Headache *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Hemiparesis *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Partial seizures *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Postictal paralysis *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Somnolence *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Status epilepticus *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Psychiatric disorders       
Agitation *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Conversion disorder *  1/125 (0.80%)  1 1/125 (0.80%)  1 1/150 (0.67%)  1
Renal and urinary disorders       
Haematuria *  0/125 (0.00%)  0 1/125 (0.80%)  1 0/150 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Acute respiratory failure *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Apnoea *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Atelectasis *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Mediastinal haemorrhage *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Obstructive airways disorder *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Pneumonia aspiration *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Respiratory acidosis *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Respiratory depression *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Respiratory distress *  1/125 (0.80%)  1 0/125 (0.00%)  0 0/150 (0.00%)  0
Upper airway obstruction *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Skin and subcutaneous tissue disorders       
Pruritus *  2/125 (1.60%)  2 0/125 (0.00%)  0 0/150 (0.00%)  0
Vascular disorders       
Deep vein thrombosis *  0/125 (0.00%)  0 0/125 (0.00%)  0 1/150 (0.67%)  1
Hypotension *  7/125 (5.60%)  7 1/125 (0.80%)  1 4/150 (2.67%)  4
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Jordan Elm, PhD Biostatistician
Organization: Medical University of South Carolina
Phone: 843-876-1605
EMail: elmj@musc.edu
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Jaideep Kapur, MD, University of Virginia
ClinicalTrials.gov Identifier: NCT01960075    
Other Study ID Numbers: 18078
119756 ( Other Identifier: ClinicalTrials.gov )
U01NS088034 ( U.S. NIH Grant/Contract )
First Submitted: October 8, 2013
First Posted: October 10, 2013
Results First Submitted: December 30, 2019
Results First Posted: February 28, 2020
Last Update Posted: June 14, 2021