A Phase 3 interventional study of Fosphenytoin and Levetiracetam in Benzodiazepine Refractory Status Epilepticus, sponsored by University of Virginia. Completed at 65 sites in United States. Open to participants aged 2 Years and older. Per ClinicalTrials.gov, last updated 2021-06-14.
Sponsored by University of Virginia · Phase 3, Interventional, and Treatment
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.
126 studies on the registry are indexed under Status Epilepticus; 37 are open to participants now.
This study's enrollment of 478 is above the median of 70 across 74 interventional studies indexed under Status Epilepticus.
Browse Status Epilepticus studies →University of Virginia is the lead sponsor of 653 studies on the registry; 134 are open to participants now.
Of its 60 completed or terminated interventional studies of FDA-regulated products, 41 (68%) have results posted.
Counted across the registry records on this site, refreshed daily.
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
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
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
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
Number of Participants With Clinical Cessation of Status Epilepticus - Intention to Treat
Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. Intention to treat
Time frame: Within 60 minutes after the start of study drug infusion
Number of Participants With Clinical Cessation of Status Epilepticus - Per-protocol Analysis
Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. Per-protocol analysis
Time frame: Within 60 minutes after the start of study drug infusion
Number of Participants With Clinical Cessation of Status Epilepticus - Adjudicated Outcomes Analysis
Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. The Adjudicated outcomes analysis is different from Outcome measure 1 because a central clinical phenomenology core of four neurologists adjudicated from the medical records the time to seizure cessation, the time in status epilepticus before trial-drug initiation, and the cause of the seizure. For each enrollment, two neurologists from this core group conducted independent initial reviews and then determined a consensus or consulted a third adjudicator, as needed. Adjudicators were unaware of the treatment assignments and made determinations by medical record review.
Time frame: Within 60 minutes after the start of study drug infusion
Number of Participants With Admission to Intensive Care Unit
ICU admission is recorded as occurring only if the ICU is the initial inpatient unit for the patient.
Time frame: Admission to intensive care unit after start of study drug infusion, where the ICU is the initial inpatient unit for the patient
Length of ICU Stay
Length of stay is determined by the number of calendar days after the day of ED arrival until hospital discharge or subject end-of-study.
Time frame: number of calendar days after the day of ED arrival until hospital discharge or subject end-of-study
Minutes From Start of Trial Drug Infusion to Termination of Seizures for Patients With Treatment Success
The time to termination of seizures is the interval from the start of study drug infusion to cessation of clinically apparent seizure in those who meet the primary outcome.
Time frame: start of drug infusion to seizure cessation
Number of Participants With Seizure Cessation Within 20 Minutes for Patients With Treatment Success
Number of participants with seizure cessation within 20 minutes of study drug initiation for patients with treatment success. This outcome measure was only reported in the Supplementary materials to the Primary Paper.
Time frame: within 20 minutes
Length of Hospital Stay
Length of hospital stay in days
Time frame: length of hospital stay
Number of Participants With Safety Outcome: Life Threatening Hypotension
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
Number of Participants With Safety Outcome: Life-threatening Cardiac Arrhythmia
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
Number of Participants With Safety Outcome: Endotracheal Intubation
Endotracheal intubation within 60 minutes of start of study drug infusion
Time frame: within 60 minutes of start of study drug infusion
Number of Participants With Safety Outcome: Acute Anaphylaxis
Acute anaphylaxis is defined as a clinical presentation consistent with life threatening allergic reaction occurring within 6 hours of the start of study drug infusions and manifested as urticaria in combination with either (1) a systolic blood pressure of \< 90 mmHg sustained for greater than 5 minutes, or (2) objective evidence of airway obstruction, and for which the patient was treated with antihistamines and/or steroids.
Time frame: within 6 hours of the start of study drug infusions
Number of Participants With Safety Outcome: Acute Respiratory Depression
Respiratory depression is defined as impairment of ventilation or oxygenation necessitating definitive endotracheal intubation and mechanical ventilation. It is distinct from intubations performed only for airway protection in those with decreased levels of consciousness. It does not include those getting only supraglottic airways or transient bag-valve-mask support.
Time frame: 24 hours
Number of Participants With Safety Outcome: Hepatic Transaminase or Ammonia Elevations
Safety outcome: Hepatic transaminase or ammonia elevations
Time frame: 24 hours
Number of Participants With Safety Outcome: Purple Glove Syndrome
Purple glove syndrome is defined as the presence of all three of the findings of the objective edema: discoloration, and pain in the distal extremity in which study drug was administered, with or without known extravasation, and for which there is no other evident etiology.
Time frame: 24 hours
Number of Participants With Safety Outcome: Death
Safety outcome: Death
Time frame: 30 days
Number of Participants With Safety Outcome: Acute Seizure Recurrence
acute seizure recurrence 60 minutes to 12 hours after start of study drug infusion
Time frame: 60 minutes to 12 hours after start of study drug infusion
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).
| Milestone | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Started | 149 | 149 | 180 |
| Completed | 141 | 146 | 173 |
| Not completed | 8 | 3 | 7 |
Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. Intention to treat
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Clinical Cessation of Status Epilepticus - Intention to Treat | 53 | 56 | 68 |
Determined by the absence of clinically apparent seizures and improving consciousness at 1 hour without other anticonvulsant medications. Per-protocol analysis
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Clinical Cessation of Status Epilepticus - Per-protocol Analysis | 37 | 43 | 51 |
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.
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Clinical Cessation of Status Epilepticus - Adjudicated Outcomes Analysis | 57 | 60 | 67 |
ICU admission is recorded as occurring only if the ICU is the initial inpatient unit for the patient.
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Admission to Intensive Care Unit | 70 | 71 | 87 |
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.
| days | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Length of ICU Stay | 1 (0 to 3) | 1 (0 to 3) | 1 (0 to 3) |
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.
| minutes | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Minutes From Start of Trial Drug Infusion to Termination of Seizures for Patients With Treatment Success | 11.7 (7.5 to 20.9) | 7.0 (4.6 to 14.9) | 10.5 (5.7 to 15.5) |
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.
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Seizure Cessation Within 20 Minutes for Patients With Treatment Success | 43 | 43 | 53 |
Length of hospital stay in days
| days | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Length of Hospital Stay | 3 (1 to 6) | 3 (2 to 6) | 3 (1 to 7) |
Life-threatening hypotension within 60 minutes of the start of study drug infusion
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Safety Outcome: Life Threatening Hypotension | 4 | 2 | 1 |
Life-threatening cardiac arrhythmia within 60 minutes of the start of study drug infusion
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Safety Outcome: Life-threatening Cardiac Arrhythmia | 0 | 0 | 1 |
Endotracheal intubation within 60 minutes of start of study drug infusion
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Safety Outcome: Endotracheal Intubation | 33 | 21 | 30 |
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.
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Safety Outcome: Acute Anaphylaxis | 0 | 0 | 0 |
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.
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Safety Outcome: Acute Respiratory Depression | 16 | 10 | 12 |
Safety outcome: Hepatic transaminase or ammonia elevations
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Safety Outcome: Hepatic Transaminase or Ammonia Elevations | 0 | 1 | 1 |
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.
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Safety Outcome: Purple Glove Syndrome | 0 | 0 | 0 |
Safety outcome: Death
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Safety Outcome: Death | 3 | 2 | 7 |
acute seizure recurrence 60 minutes to 12 hours after start of study drug infusion
| Participants | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| Number of Participants With Safety Outcome: Acute Seizure Recurrence | 14 | 14 | 16 |
Collected over Data on adverse events were collected through the first 24 hours after enrollment, for the duration of the trial.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Fosphenytoin (FOS) | 3/125 (2.4%) | 57/125 (45.6%) | 28/125 (22.4%) |
| Valproic Acid | 2/125 (1.6%) | 46/125 (36.8%) | 22/125 (17.6%) |
| Levetiracetam | 7/150 (4.7%) | 64/150 (42.7%) | 25/150 (16.7%) |
| Event | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| ConvulsionNervous system disorders | 25/125 | 23/125 | 30/150 |
| Respiratory depressionRespiratory, thoracic and mediastinal disorders | 15/125 | 8/125 | 10/150 |
| Depressed level of consciousnessNervous system disorders | 12/125 | 9/125 | 15/150 |
| HypotensionVascular disorders | 7/125 | 6/125 | 4/150 |
| Respiratory failureRespiratory, thoracic and mediastinal disorders | 2/125 | 4/125 | 1/150 |
| EncephalopathyNervous system disorders | 0/125 | 1/125 | 4/150 |
| PneumoniaInfections and infestations | 2/125 | 2/125 | 4/150 |
| RhabdomyolysisMusculoskeletal and connective tissue disorders | 0/125 | 0/125 | 3/150 |
| Cerebral infarctionNervous system disorders | 2/125 | 1/125 | 0/150 |
| Deep vein thrombosisVascular disorders | 0/125 | 2/125 | 1/150 |
| Event | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam |
|---|---|---|---|
| ConvulsionNervous system disorders | 3/125 | 8/125 | 4/150 |
| HypotensionVascular disorders | 7/125 | 1/125 | 4/150 |
| HypophosphataemiaMetabolism and nutrition disorders | 0/125 | 3/125 | 1/150 |
| HypocalcaemiaMetabolism and nutrition disorders | 0/125 | 2/125 | 3/150 |
| PyrexiaGeneral disorders | 2/125 | 1/125 | 3/150 |
| FallInjury, poisoning and procedural complications | 2/125 | 0/125 | 0/150 |
| HypomagnesaemiaMetabolism and nutrition disorders | 0/125 | 2/125 | 0/150 |
| PruritusSkin and subcutaneous tissue disorders | 2/125 | 0/125 | 0/150 |
| VomitingGastrointestinal disorders | 1/125 | 2/125 | 2/150 |
| Troponin increasedInvestigations | 0/125 | 1/125 | 2/150 |
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(years) | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam | Total |
|---|---|---|---|---|
| Mean | 32.8 ± 25.4 | 32.2 ± 25.4 | 33.3 ± 26.0 | 32.8 ± 25.6 |
| Age, Customized(Participants) | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam | Total |
|---|---|---|---|---|
| Age — 0 - 5 yr | 24 | 28 | 30 | 82 |
| Age — 6 - 10 yr | 15 | 7 | 17 | 39 |
| Age — 11 - 20 yr | 10 | 18 | 9 | 37 |
| Age — 21 - 40 yr | 20 | 19 | 31 | 70 |
| Age — 41 - 60 yr | 26 | 26 | 34 | 86 |
| Age — => 61 yr | 23 | 23 | 24 | 70 |
| Sex: Female, Male(Participants) | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam | Total |
|---|---|---|---|---|
| Female | 47 | 56 | 68 | 171 |
| Male | 71 | 65 | 77 | 213 |
| Race/Ethnicity, Customized(Participants) | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam | Total |
|---|---|---|---|---|
| Race/Ethnicity — Black | 49 | 54 | 62 | 165 |
| Race/Ethnicity — White | 49 | 49 | 62 | 160 |
| Race/Ethnicity — Other, >1 race, or unknown | 20 | 18 | 21 | 59 |
| Race/Ethnicity, Customized(Participants) | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam | Total |
|---|---|---|---|---|
| Hispanic Ethnicity | 18 | 22 | 23 | 63 |
| Prior history of epilepsy(Participants) | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam | Total |
|---|---|---|---|---|
| Count of participants | 80 | 83 | 97 | 260 |
| Final Diagnosis(Participants) | Fosphenytoin (FOS) | Valproic Acid | Levetiracetam | Total |
|---|---|---|---|---|
| Seizure/Status Epilepticus | 104 | 102 | 128 | 334 |
| Non-epileptic spell | 11 | 13 | 13 | 37 |
| Unable to adjudicate | 3 | 6 | 4 | 13 |
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