Status Epilepticus
Conditions
Brief summary
The goal of this clinical trial is to determine if treatment of patients with two doses of ketamine plus levetiracetam versus levetiracetam alone leads to more effective control of status epilepticus.
Detailed description
KESETT is a multicenter, randomized, blinded study to determine whether adding 1 mg/kg or 3 mg/kg dose of KET to 60 mg/kg LEV can terminate status epilepticus (SE) in a larger fraction of subjects with benzodiazepine-refractory SE than those treated with LEV (60 mg/kg) alone. The primary outcome is termination of SE from 15 minutes after starting the study drug infusion, sustained until 60 minutes from enrollment without using additional anti-seizure medication. Termination of SE is determined by (1) improving consciousness and absence of clinically apparent seizures at 60 minutes or (2) absence of any electrographic SE after 15 minutes in those with EEG monitoring and no improvement in consciousness. Secondary objectives include determining the relative safety of the treatment arms on defined safety outcomes and all adverse events, analysis of secondary/exploratory efficacy outcomes, and evaluation of both effectiveness and safety in the pediatric subpopulation. The trial will initially allocate subjects equally (1:1:1) for the first 350 participants (burn-in period) before transitioning to response-adaptive randomization. Interim analyses will be conducted for efficacy and futility beginning when 350 subjects have been randomized, and will occur every 100 subjects thereafter. A maximum of 770 participants will be enrolled.
Interventions
DRUGLevetiracetam (LEV) (60 mg/Kg) + 1 mg/kg Ketamine (KET)
The study drug will be produced at the central pharmacy, a GMP facility at the University of California, Davis. Diluted formulations are expected to remain stable for months when stored at room temperature. Expiration dates for study drugs will be determined and adjusted based on ongoing stability testing performed on study drugs prepared at the GMP facility for the study. All three formulations will be transparent solutions. None of the formulations are reported to consistently cause adverse effects at the infusion site. The method of drug administration, including volume and rate of infusion, is identical for all three drugs. These factors ensure that drug administration will be blinded.
DRUGLevetiracetam (LEV) (60 mg/Kg) + 3 mg/kg Ketamine (KET)
The study drug will be produced at the central pharmacy, a GMP facility at the University of California, Davis. Diluted formulations are expected to remain stable for months when stored at room temperature. Expiration dates for study drugs will be determined and adjusted based on ongoing stability testing performed on study drugs prepared at the GMP facility for the study. All three formulations will be transparent solutions. None of the formulations are reported to consistently cause adverse effects at the infusion site. The method of drug administration, including volume and rate of infusion, is identical for all three drugs. These factors ensure that drug administration will be blinded.
DRUGLevetiracetam (LEV) (60 mg/Kg)
The study drug will be produced at the central pharmacy, a GMP facility at the University of California, Davis. Diluted formulations are expected to remain stable for months when stored at room temperature. Expiration dates for study drugs will be determined and adjusted based on ongoing stability testing performed on study drugs prepared at the GMP facility for the study. All three formulations will be transparent solutions. None of the formulations are reported to consistently cause adverse effects at the infusion site. The method of drug administration, including volume and rate of infusion, is identical for all three drugs. These factors ensure that drug administration will be blinded.
Sponsors
University of Virginia
University of Michigan
Medical University of South Carolina
Massachusetts General Hospital
Children's National Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The patient was witnessed to have a convulsive seizure for greater than 5-minute duration * The patient received an adequate dose of benzodiazepines. The doses may be divided. * The last dose of a benzodiazepine was administered 5-30 minutes before study drug administration. * Continued or recurring seizures in the Emergency Department. * Age 1 years or older * Known or estimated weight ≥10 Kg
Exclusion criteria
* Known pregnancy * Prisoner * Opt-out identification or otherwise known to be previously enrolled in KESETT * 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 for this episode of SE(propofol, etomidate, ketamine or other agents defined in the MoP) * Endotracheal intubation prior to enrollment * Acute traumatic brain injury clearly precedes seizures * Scalp injury or burn preventing EEG placement * Known allergy or other known contraindication to KET or LEV * Hypoglycemia \< 50 mg/dL * Hyperglycemia \> 400 mg/dL * Cardiac arrest / post-anoxic seizures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Termination of SE | From 15 minutes after starting the study drug infusion, sustained for 60 minutes without using additional anti-seizure medication. | Termination of SE from 15 minutes after starting the study drug infusion, sustained for 60 minutes without using additional anti-seizure medication. Termination of SE is determined by (1) improving consciousness and absence of clinically apparent seizures at 60 minutes or (2) absence of any electrographic status epilepticus (ESE) after 15 minutes in those with EEG monitoring and no improvement in consciousness. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Desirability of response (DOOR) outcome | 60 minutes after starting the study drug infusion | One secondary outcome will be a desirability of response (DOOR) outcome which is a composite efficacy measure evaluated on a graded scale from 1 to 5 at 60 minutes, as follows: * No clinically evident or electrographic seizures after 15 minutes, no rescue drugs, and improving mental status by 60 minutes * No clinically evident or electrographic seizures after 15 minutes, not intubated, but not improving mental status at 60 minutes * No clinically evident or electrographic seizures after 15 minutes, but intubated or use of additional seizures medications (including medications used for intubation) * Any clinically evident seizure or electrographic seizure requiring rescue medicine within the timeframe between 15 and 60 minutes * Life-threatening hypotension or cardiac arrhythmia or death within 60 minutes The Central Adjudication Core will determine the DOOR grade (1-5) based on clinical outcome data provided by the site and EEG data provided by the Central EEG Core. |
| Endotracheal intubation | Within 60 minutes after start of the study drug infusion | Endotracheal intubation within 60 minutes of randomization (start of study drug infusion) and duration |
| ICU duration | Up to 30 days after enrollment | ICU duration during the study period for those that are admitted to the ICU as abstracted from the hospital admission record |
| Hospital length-of-stay (LOS) | Up to 30 days after enrollment | Hospital length-of-stay (LOS) from the ED as abstracted from the hospital admission record |
| Late recurrent seizure | Between 60 minutes and 4 hours after the start of the study drug infusion | Number of participants with late recurrent seizure between 60 minutes and 4 hours after the start of the study drug infusion |
| Time to termination of seizures | From the start of infusion of study drug to the cessation of electrographic seizure assessed up to 60 minutes from study drug initiation | The interval from the start of infusion of study drug to the cessation of electrographic seizure in those who meet the primary outcome |
| Late seizures after requiring an anesthetic | Between 60 minutes and 24 hours after start of study drug infusion | Number of participants with late seizures after requiring an anesthetic between 60 minutes and 24 hours after start of study drug infusion |
| All cause mortality | From the start of study drug infusion to hospital discharge or day 30 | All cause mortality to end of study |
Countries
United States
Contacts
CONTACTMegan Wardius
PRINCIPAL_INVESTIGATORJaideep Kapur, MD, PhD
University of Virginia
Outcome results
None listed