UG3NS131532

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.

Rector & Visitors Of The University Of Virginia

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Virginia United States

State-Wide

NINDS Efficacy Clinical Trials (UG3/UH3 Clinical Trial Required) (PAR-21-237)