Ketamine add-on Therapy for Established Status Epilepticus Treatment Trial (KESETT)

Phase 3

Not yet recruiting

• Conditions: Status Epilepticus
• Interventions: Drug: Levetiracetam (LEV) (60 mg/Kg); Drug: Levetiracetam (LEV) (60 mg/Kg) + 1 mg/kg Ketamine (KET); Drug: Levetiracetam (LEV) (60 mg/Kg) + 3 mg/kg Ketamine (KET)

• Registration Number: NCT06907173
• Lead Sponsor: University of Virginia

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.

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-24
• Study First Submitted QC: 2025-03-31
• Last Update Submitted: 2025-03-31
• Study First Posted: 2025-04-02
• Last Update Posted: 2025-04-02
• Study Start: 2025-08
• Primary Completion: 2029-06
• Study Completion: 2029-12

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 770

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Levetiracetam	Levetiracetam (LEV) (60 mg/Kg)	Levetiracetam (LEV) (60 mg/Kg)
Levetiracetam + low dose Ketamine	Levetiracetam (LEV) (60 mg/Kg) + 1 mg/kg Ketamine (KET)	LEV 60 mg/mL + 1 mg/mL KET
Levetiracetam + high dose Ketamine	Levetiracetam (LEV) (60 mg/Kg) + 3 mg/kg Ketamine (KET)	LEV 60 mg/mL + 3 mg/mL KET increasing up to a weight of 75 kg

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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