Trial Summaries

In Progress              

In Development              

Completed

 

 

In Progress:

BOOST-3 - Brain Oxygen Optimization in Severe TBI Phase-3

PI: Ramon Diaz-Arrastia, MD, PhD - University of Pennsylvania

Status: Approved, preparing to enroll

Traumatic brain injury (TBI) is a major cause of death and disability. Of the 3.5 million Americans who sustain a TBI every year, approximately 27,000 experience prolonged traumatic coma, the most severe form of TBI. Less than 20% of these patients make a good recovery, and most are left with life-long disabilities. ICU management of severe TBI focuses on monitoring intracranial pressure (ICP), but data from recently conducted randomized clinical trials indicate that this approach is overly simplistic. Another approach is to monitor the partial pressure of oxygen in brain tissue (PbtO2), and apply interventions to prevent brain tissue hypoxia and improve neurologic outcome. Clinical studies demonstrate that brain tissue hypoxia is common, that there is a strong relationship between low PbtO2 and poor outcome, and that timely interventions can reverse brain tissue hypoxia. The first randomized controlled trial of PbtO2 monitoring in severe TBI, titled “Brain Oxygen Optimization in Severe TBI (BOOST) Phase 2,” enrolled 122 subjects, and demonstrated that the mean hypoxia burden was reduced by 74% by the treatment protocol informed by PbtO2 monitoring (p < 0.0001), and there were no significant safety issues. There was a trend towards improved functional outcome, supporting the pre-determined non-futility hypothesis. We are proposing the BOOST-3 trial to determine if there is evidence of clinical efficacy of a treatment protocol based on PbtO2 monitoring compared to treatment based on ICP monitoring alone. BOOST-3 will enroll patients with severe TBI requiring placement of ICP monitors within 6 hours of injury. Patients will be randomized to a treatment protocol based on ICP monitoring alone or the combination of ICP and PbtO2 monitoring. The Glasgow Outcome Scale-Extended (GOS-E) measured at 6 months post injury will be the primary outcome. Other secondary outcomes include functional, cognitive and behavioral assessments at 6 months, safety, survival to discharge, shortened time to follow commands, and reduction of total brain hypoxia exposure. 

 

ESETT - Established Status Epilepticus Treatment Trial

PIs: Jaideep Kapur, MD - University of Virginia

Status: Funded, enrolling

Synopsis

The Established Status Epilepticus Treatment Trial (ESETT) is a multicenter, randomized, double-blind, comparative effectiveness study of fos-phenytoin, levetiracetam, and valproic acid in subjects with benzodiazepine-refractory status epilepticus. Patients will be recruited by two national emergency research networks:  Neurology Emergency Treatment Trials (NETT) network and Pediatric Emergency Care and Applied Research Network (PECARN).  Each network has successfully undertaken a Status Epilepticus treatment trial under exception from informed consent (EFIC) rules.

 

HOBIT - Hyperbaric Oxygen Brain Injury Treatment Trial

PI: Gaylan L. Rockswold, MD - Hennepin County Medical Center

Status: Funded, preparing to enroll

Preclinical and clinical investigations (discussed below) strongly indicate that HBO2 is physiologically active in reducing brain injury and improving outcomes in severe TBI. However, prior to a definitive efficacy study, important information is required regarding optimizing the HBO treatment paradigm instituted in terms of pressure and frequency of HBO2 treatments and whether NBH enhances the clinical effectiveness of the HBO2 treatment. Preclinical investigators working with TBI models have used pressures varying from 1.5 to 3.0 atmospheres absolute (ATA). Clinical investigators have used pressure varying from 1.5 to 2.5 ATA. However, the lungs in severe TBI patients have frequently been compromised by direct lung injury and/or acquired ventilator pneumonia and are susceptible to oxygen (O2) toxicity. Working within these constraints, it is essential to determine the most effective HBO2 dose schedule without producing O2 toxicity and clinical complications. This proposed clinical trial is designed to answer these questions and to provide important data to plan a definitive efficacy trial.

 

POINT - Platelet-Oriented Inhibition in New TIA Trial

PI: Clay Johnston, MD - University of California, San Francisco

Status: Funded, enrolling

Transient ischemic attacks (TIA) are common, with an estimated 250,000-350,000 occurring each year in the US, an incidence about 30-40% that of stroke.  Rapid recovery of cerebral ischemia (reduction of blood flow to the brain) is a defining characteristic of TIA and distinguishes it from completed stroke.  This recovery defines a distinct pathophysiologic feature that generally indicates the presence of previously ischemic tissue still at risk: a characteristic that may be responsible for greater instability. In fact, numerous studies have shown that short-term risk of stroke is high after TIA, particularly in the first few days, even in patients treated with aspirin, the current standard of care. Antithrombotic therapy may play a distinct role in this acute pathophysiology. Effective therapies in those with TIA could significantly reduce the overall burden of stroke if initiated immediately. However, no large-scale trial has evaluated an acute intervention in patients with TIA.

The Primary Specific Aim of this randomized, double-blind, multicenter clinical trial is to determine whether clopidogrel (Plavix) 75 mg/day by mouth after a loading dose of 600 mg is effective in reducing the 90-day risk of major ischemic vascular events (ischemic stroke, myocardial infarction, and ischemic vascular death) when initiated within 12 hours of TIA onset in patients receiving aspirin 50-325 mg/day.

 

SHINE - Stroke Hyperglycemia Insulin Network Effort

PI: Karen Johnston, MD - University of Virginia

Status: Funded, enrolling

This is a multicenter, prospective, randomized, controlled trial, with blinded outcomes. It aims to determine the efficacy and provide further safety data on the use of insulin infusion therapy for glucose control in hyperglycemic acute ischemic stroke patients. Treatment with insulin infusion will be given within 12 hours of symptom onset. The primary outcome to be assessed at 90 days will be the difference in favorable outcome measured by the modified Rankin Scale score in the insulin infusion group compared to the control group. The rates of symptomatic hypoglycemia with prolonged neurological worsening as well as asymptomatic hypoglycemia will be assessed. The secondary outcomes will assess additional neurological and functional outcomes. This highly collaborative research program is nearly guaranteed to advance the field of stroke care.

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In Development:

ARCTIC - Acute Rapid Cooling for Therapy for Injuries of the Spinal Cord

PI: Michael Wang, MD, FACS - University of Miami

Status: In development

Synopsis

Traumatic spinal cord injury affects an estimated 11,000 people in the United States each year, most commonly affecting young adults in the prime of their life. Advances in the medical management of this patient population have resulted in improvements in the survivability of these injuries, with a majority of patients having a near-normal life expectancy. Thus, because of its devastating consequences but high likelihood of long-term survivability, exerts a disproportionate medical, social and economic toll. A great deal of research has been directed at identifying interventions which may mitigate the secondary mechanisms which lead to neurological worsening and impede native recovery. However, to date there have been no clinical trials definitively demonstrating the efficacy of acute interventions to improve neurological outcomes in humans with traumatic spinal cord injuries.

The SIREN-NETT network has proposed a randomized, controlled, multi-center study to investigate the efficacy of modest intravascular hypothermia (33.5 + 0.2° C) for improving neurological function following both complete and incomplete spinal cord injuries in humans. Significant improvement will be determined by a greater than 10 point difference between the two treatment arms in the mean change in motor score as determined at 12 month follow-up. Additional outcome measures will include ASIA sensory scores and measures of pain and disability. It is anticipated that such a study will answer the question of whether emergent intravascular cooling, a method which has shown promise in the laboratory, can improve the neurological function and independence of patients suffering from spinal cord injuries.

 

CHEST PAIN - Comparative Health Effectiveness of Strategies Testing Pain Assessment of Ischemia Noninvasively

PI: Clifton Callaway, MD - University of Pittsburgh

Status: In development

Emergency department (ED) evaluation of patients with possible acute coronary syndrome (ACS) is frequent and costly.  Of 8-10 million annual ED presentations for chest pain, 40% or more will be deemed low-risk after initial evaluation.  Yet the majority of these patients receive in-hospital noninvasive testing during their index visit.  The proposed study will directly test whether in-hospital evaluation and noninvasive testing should be part of the standard approach to low-risk patients.

The CHEST PAIN trial will be a multicenter randomized controlled non-inferiority trial comparing an in-hospital noninvasive testing strategy versus an outpatient follow-up strategy among patients evaluated for possible ACS who meet a standard low-risk definition (proposed sample size ~16,700 subjects).  The in-hospital strategy will consist of standard care with intent to perform a noninvasive test prior to discharge from the hospital.  The outpatient strategy will consist of discharge from the ED within six hours of being seen by an ED physician with outpatient follow-up within seven days.

 

ICECAP - Influence of Cooling Duration On Efficacy in Cardiac Arrest Patients 

PI: Not assigned

Status: In development

Synopsis

Neurological death and disability are common outcomes in survivors of cardiac arrest. Therapeutic cooling of comatose patients resuscitated from shockable rhythyms has been shown in two randomized controlled trials to markedly increase the rate of good neurological outcome, but the optimal duration of induced hypothermia has not been investigated. ICECAP is a randomized adaptive clinical trial to characterize the duration‐response curve of induced hypothermia in comatose survivors of cardiac arrest and to determine the optimal duration of cooling. Subjects will initially be randomized to 12, 24, or 48 hours of cooling. After 150 subjects have been enrolled, response adaptive randomization will allocate subjects to a shorter duration (6 hours) if the developing model suggests a flat durationresponse curve, or to longer durations (60 or 72 hours) if the developing model suggests a positive but not yet plateauing duration‐response curve, and to the original and interposed durations (18, 30, 36, 42 hours) as needed to refine the model. Comatose adult survivors of cardiac arrest from shockable rythyms that have already been rapidly cooled using a definitive temperature control method (endovascular or surface) will be enrolled. The primary outcome will be modified Rankin score at 90 days analyzed as a weighted score incorporating both the proportion of subjects achieving a good neurological outcome and degree of residual functional impairment among those with good neurological outcomes.

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Completed:

ALIAS - Albumin Therapy for Neuroprotection in Acute Ischemic Stroke 

PI: Myron Ginsberg, MD - University of Miami

Status: Complete

The purpose of the ALIAS trial was to evaluate the effectiveness of high-dose, intravenous human serum albumin.  Human serum albumin is a natural protein already in clinical use for a variety of indications.  In animal laboratory studies it has been shown that it reduces the size of the infarction (amount of tissue death) in the brain and improves neurological function after a stroke and also decreases or eliminates the brain swelling that may occur; these effects may reduce or prevent the brain damage resulting from a stroke in humans.

 

ATTACH-II - Antihypertensive Treatment of Cerebral Hemmorrhage

PI: Adnan Qureshi - University of Minnesota

Status: Funded, enrolling

ATACH-II is a five-year, multi-center, randomized, controlled, Phase-III trial with blinded outcome ascertainment to determine the efficacy of early, intensive antihypertensive treatment using intravenous nicardipine for acute hypertension in subjects with spontaneous supratentorial intracerebral hemorrhage (ICH).  The ATACH-II clincial trial is funded by the National Institute of Neurological Disorders and Stroke part of the National Institutes of Health.

The primary hypothesis of this large, streamlined, focused trial is that intensive systolic blood pressure (SBP) reduction using intravenous (IV) nicardipine with treatment initiated within three (3) hours of onset of ICH and continued for the next 24 hours reduces the likelihood of death or disability at three (3) months after ICH by ten percent (10%) or greater compared with standard SBP reduction.  The underlying mechanism for this expected beneficial effect of intensive treatment is presumably mediated through reduction of the rate and magnitude of hematoma expansion observed in approximately seventy-three percent (73%) of patients with acute ICH.

ATACH-II will recruit a maximum of 1,280 subjects with ICH who meet the eligibility criteria.  The trial will have important public health implications as it will provide necessary information regarding the efficacy and safety of antihypertensive treatment of acute hypertension in subjects with ICH.  BP treatment represents a strategy that can be made widely available without the need of specialized equipment and personnel, and therefore can make a major impact upon outcome in patients with ICH.

 

RAMPART - Rapid Anticonvulsant Medication Prior to Arrival Trial

PI: Robert Silbergleit, MD - University of Michigan

Status: Complete

Status epilepticus, a condition of persistent seizures that do not stop, is a true neurologic emergency associated with significant death and disability.  Paramedics treat status epilepticus with anti-seizure medicine, but giving medicine through a vein can be difficult or slow in a seizing patient.  This study was done to determine (1) if the anti-seizure drug midazolam given as a shot in the muscle stops seizures as well as the anti-seizure medicine lorazepam given directly into a vein, and (2) the rapidity and safety of these two medicines given in these different ways.  The RAMPART study was conducted using special rules for studies in which the subjects are too sick or incapacitated to either agree to or decline to participate at the time they are being treated in the ambulance or in the Emergency Room.

 

ProTECT - Progesterone for Traumatic Brain Injury: Experimental Clinical Treatment

PI: David Wright, MD - Emory University

Status: Complete

Traumatic brain injury (TBI) is a major cause of premature death and disability worldwide.  With the exception of mannitol, no therapy has been found to be effective in reducing mortality and improving functional outcomes.  Progesterone is a steroid found to have powerful neuroprotective properties in multiple different animal models of brain injury.  Based on encouraging pilot clinical trial results, the ProTECT trial's objective was to determine the efficacy and confirm safety of this treatment in adults with moderate to severe TBI.

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