Current Studies

There continues to be an overarching problem of high mortality and poor outcome for victims of severe traumatic brain injury (TBI). Preclinical and clinical investigations indicate that hyperbaric oxygen (HBO2) has a positive impact on reducing brain injury and improving outcomes in severe TBI. By markedly increasing oxygen (O2) delivery to the traumatized brain, HBO2 can reverse the lack of O2 that precipitates cellular energy failure and subsequent brain cell death. In past clinical investigations, HBO2 in comparison to standard care has significantly improved energy production in the brain and improved clinical outcome. However, prior to a formal phase III definitive efficacy study, important information is required regarding optimizing the HBO2 treatment schedule to be instituted in terms of pressure and frequency and other parameters. The lungs in severe TBI patients have frequently been compromised by direct lung injury and/or acquired ventilator pneumonia and are susceptible to O2 toxicity. It is essential to determine the most effective HBO2 dose schedule without producing O2 toxicity and clinical complications.

Hyperbaric Oxygen Brain Injury Treatment Trial (HOBIT) is a proposed adaptive clinical trial designed to answer these questions and to provide important data to plan a definitive phase III efficacy trial. Primary aims of this trial are to select, patients with severe TBI, the combination of HBO2 treatment parameters that is most likely to demonstrate improvement in the outcome of severe TBI patients in a subsequent phase III trial. Also, the trial will determine, patients with severe TBI, whether there is a > 50% probability of HBO2 treatment demonstrating improvement in the outcome of severe TBI in a subsequent confirmatory phase III trial. This trial will enroll 200 subjects over 3 1/2 years. This trial is supported and sponsored by the SIREN-NETT Network which is funded by the National Institutes of Neurologic Disease and Stroke to conduct clinical trials such as the one described.

Learn more at: https://siren.network/clinical-trials/hobit

Traumatic brain injury (TBI) is a major cause of death and disability in developed societies. Every year, approximately 3.5 million Americans sustain a TBI, of which 50,000 die, and another 300,000 are hospitalized and survive the injury.  BOOST3 is a randomized clinical trial to determine the comparative effectiveness of two strategies for monitoring and treating patients with traumatic brain injury (TBI) in the intensive care unit (ICU). The study will determine the safety and efficacy of a strategy guided by treatment goals based on both intracranial pressure (ICP) and brain tissue oxygen (PbtO2) as compared to a strategy guided by treatment goals based on ICP monitoring alone. Both of these alternative strategies are used in standard care. It is unknown if one is more effective than the other. In both strategies the monitoring and goals help doctors adjust treatments including the kinds and doses of medications and the amount of intravenous fluids given, ventilator (breathing machine) settings, need for blood transfusions, and other medical care. The results of this study will help doctors discover if one of these methods is more safe and effective.

Learn more at: https://siren.network/clinical-trials/boost-3

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.

Learn more at: https://siren.network/trial/kesett/