Ketamine Add-On for Established Status Epilepticus Treatment Trial (KESETT)

The Ketamine add-on therapy for Established Status Epilepticus Treatment Trial (KESETT) is a phase III randomized, double-blind clinical trial to test whether ketamine (KET) (1 or 3 mg/Kg) added to the standard therapy, levetiracetam (LEV), is more effective than levetiracetam (60 mg/Kg) alone in treating status epilepticus after benzodiazepines have failed. Generalized convulsive status epilepticus (SE) is a dangerous but common neurologic emergency; it can cause respiratory depression and permanent brain damage. Benzodiazepines are an effective first-line therapy, but approximately one-third of children and 40% of adults do not respond. Patients who fail benzodiazepines are in established status epilepticus. They are treated with second-line agents such as levetiracetam, which successfully terminates status epilepticus in only 47% of subjects. We propose that adding ketamine to levetiracetam will increase efficacy to 62%. Preclinical and clinical evidence supports this trial. Ketamine, an NMDA receptor antagonist, terminates benzodiazepine refractory SE in experimental animals. NMDA receptor activation triggers self-reinforcing seizure mechanisms underlying SE. It abrogates inhibitory plasticity, prevents excitotoxicity and neuronal death, and prevents epileptogenesis accompanying SE in experimental animals. Recent clinical studies in children and adults showed that ketamine terminated established status epilepticus in 23 of 24 subjects. Ketamine is used extensively in emergency settings for sedation, intubation, agitation, and pain management; it is on the WHO essential medications list because it is safely used extensively. Clinicians use it effectively to treat refractory and super-refractory SE, and many experts recommend it. ED physicians have used it for decades for procedural sedation. We propose to test 1 and 3 mg/kg ketamine doses based on recent human studies, extensive pharmacokinetic modeling, animal-to-human dose conversion as suggested by the FDA, and data on the safety of ketamine. Our overall hypothesis is that ketamine added to LEV will improve the outcome of established status epilepticus compared to treatment with levetiracetam alone by clinically meaningful 15%. We will test this hypothesis by accomplishing the following specific aims in a Bayesian-adaptive randomized clinical trial: Aim 1: Determine whether participants randomized to levetiracetam +3 mg/kg ketamine or Levetiracetam +1 mg/kg ketamine will have more desirable outcomes than those receiving levetiracetam +placebo. We rank the outcomes on a scale ranging from 1 to 5. Aim 2: To ensure that the trial is informative for treating established status epilepticus in children by describing the effectiveness and rate of adverse reactions of these drugs. Aim 3: Measure differences between treatment arms in secondary outcomes. This trial can change the treatment paradigm for SE by supplementing current second-line agents with ketamine to improve the timeliness of seizure termination.