The CLEAR-IVH trial, completed in 2008, was a phase 2 feasibility and dose-finding trial conducted at 20 centers in the U.S., Canada, U.K. and Germany. There were 3 phases: Safety, CLEAR A and CLEAR B. The study enrolled 52 patients with a confirmed diagnosis of intraventricular hemorrhage (IVH) with third or fourth ventricle obstruction. Patients were given a thrombolytic, recombinant tissue plasminogen activator (tPA), via an extraventricular catheter (EVD) in one of three dosing regimens over a 3-day period. Results of the study were presented by Dr. Daniel Hanley of Johns Hopkins University, lead investigator, at the 2008 European Stroke Conference in Nice, France.
The Intraventricular Hemorrhage Thrombolysis Trial was supported by grants (FD-R-001693 to Drs. Naff and Hanley; FD-R 002018 to Drs. Hanley and Rhoney) from the Office of Orphan Products Development, Food and Drug Administration. Dr. Naff received funding from the American Heart Association and funding from a research grant (FD-R-001693) from the Office of Orphan Products Development. Dr. Penelope Keyl received funding from a research grant (FD-R-001693) from the Office of Orphan Products Development. Karen Lane and Nichol McBee received funding from a research grant (FD-R-001693) from the Office of Orphan Products Development. Dr. Stanley Tuhrim received funding from a research grant (FD-R- 001693) from the Office of Orphan Products Development. Dr. Anthony Marmarou received funding from a research grant (FD-R-001693) from the Office of Orphan Products Development. Dr. Daniel Hanley is supported by grants U01NS062851 and RO1NS046309 from the National Institutes of Health/NINDS, grant 272-2007 from the Eleanor Naylor Dana Charitable Trust, the Jeffrey and Harriet Legum Endowment and materials grants from Genentech, Inc. The study results established the optimal dosage, validated the dosing procedure and provided justification for launching the large phase 3 trial, CLEAR III, in mid-2009.
ClinicalTrials.gov Identifier: NCT00784134
CLEAR III is a 500-patient phase 3 randomized clinical trial using a recombinant tissue plasminogen activator (Activase) to quickly remove blood from the ventricles. More than 70 major hospitals and academic institutions are participating in this international clinical trial as clinical sites or support teams.
CLEAR III is the culmination of 10 years of research over a number of investigational trials. The early clinical studies were supported by grants from the Food and Drug Administration Office of Orphan Products Development, the American Heart Association and other organizations. Current funding for CLEAR III is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) and from the Eleanor Naylor Dana Charitable Trust, the Jeffrey and Harriet Legum Endowment, and support from Genentech, Inc.
Having completed enrollment in CLEAR III, we are launching a clinical registry to track worldwide adoption of the therapy and techniques that were evaluated during the phase 3 clinical trial. It is our hope that this registry will help stroke researchers and scientists gain valuable information about the use of intraventricular thrombolytic therapy as it is generalized around the world to community hospitals and specialized stroke centers, many of which may not have participated in the CLEAR III clinical trial.
MISTIE is a series of clinical trials where neurosurgeons and neurologists are trying to quickly remove this blood clot from the brain using a thrombolytic (MISTIE II and MISTIE III) or a CT-guided endoscope (MISTIE-ICES).
Preliminary results from the MISTIE II trial have shown that blood clot in the brain can be successfully removed quickly and safely. These early results also suggest that the MISTIE technique reduces the rate of death and improves the patient's neurologic functioning and quality of life in the year following this type of hemorrhagic stroke. Dr. Daniel F. Hanley, co-principal investigator, presented the phase 2 results at the 2013 International Stroke Conference in Honolulu.
The MISTIE III intervention seeks to remove blood from the brain through minimally invasive surgery and intermittent dosing of a clot-busting drug, a recombinant tissue plasminogen activator (rt-PA) called alteplase, sold under the trade names of Cathflo Activase by Genentech in the U.S. and as Actilyse by Boehringer Ingelheim in Europe and Asia. The study premise is that by removing the blood clot faster, injury to the brain will be reduced and the patient’s long-term prognosis will improve.
MISTIE III is the result of over 10 years of preliminary research and clinical trials. An earlier study, MISTIE II, was completed in April 2013. That study suggested that this investigational treatment might offer a new therapy for this devastating condition. The next study, MISTIE III, was designed to confirm these preliminary findings in a larger number of patients. The hope is that the MISTIE approach can improve patients' long-term quality of life. The primary endpoint is an outcomes assessment called the modified Rankin Scale score measured at 180 and 365 days after the stroke.
Equigen is a bioequivalency trial comparing a branded vs. generic antiepileptic. The trial is being conducted at three sites, with each enrolling 12 subjects each. Johns Hopkins' Brain Injury Outcomes team is serving as coordinating center for this 18-month trial.
EQUIGEN is composed of two sister bioequivalency trials. The EQUIGEN Chronic Dose trial is comparing two generics of lamotrigine. The trial is being conducted at six sites, with each enrolling approximately 6 subjects over 12 months. The EQUIGEN Single Dose trial is comparing Lamictal with two generics of lamotrigine. The trial is being conducted at five sites, with each enrolling approximately 11 subjects over 12 months. For both trials, the University of Cincinnati has contracted with the Johns Hopkins Brain Injury Outcomes team to serve as the coordinating center and the University of Kansas Medical Center to serve as the data management center.
SMARTS is a series of studies conducted by Dr. John Krakauer at Johns Hopkins exploring how the brain changes over the first year following a stroke. Dr. Krakauer is using several non-invasive techniques, including MRI, transcranial magnetic stimulation, and measures of arm movement, to learn more about how individuals recover from a stroke. It is hoped that this information will help predict recovery and help researchers understand how changes in the brain relate to the performance of movement. This study is being conducted at Johns Hopkins Hospital and the Kennedy Krieger Institute. BIOS is providing trial coordination.
The pilot study, SMARTS-1, was conducted to evaluate and quantify the biologic factors that are associated with the natural history of recovery over stroke, and to investigate the relationship between motor learning capacity and functional recovery over the course of 12 months post-stroke.
In order to learn about recovery from stroke, noninvasive techniques including MRI, transcranial magnetic stimulation, cognitive testing, and a variety of methods of measurement of the ability to move arms was tested at 5 time-points over a year following a stroke.
This study was an observational study, conducted for the past 2 years, enrolling participants within 4-6 weeks following an acute stroke. The Hopkins researchers had considerable success with the 16 patients enrolled—10 have completed the year of testing thus far. This was a multi-center study, with additional patients enrolled at Columbia University, and in Zurich Switzerland.
SMARTS 2 will open for recruitment this summer. The premise of the new trial is that during the early period when most of a patient's spontaneous motor recovery occurs, training will have the greatest effects.
HU Prevent is a clinical study that aims to compare the drug hydroxyurea to a placebo in children with sickle cell disease. The goal of this clinical trial is to determine if hydroxyurea can prevent brain injury. Some of the most devastating complications of sickle cell disease, including stroke, silent stroke, and fast blood flow to the brain, can occur early in a child’s life. Through information gained from the HU Prevent Study, we hope to help prevent these common problems in children with sickle cell disease.
Around 25 hospitals across the country are participating in this study in an effort to improve the lives of children and families living with sickle cell disease. Johns Hopkins BIOS is serving as the national coordinating center.
DIAS-4 is a phase III study, sponsored by Lundbeck to evaluate the efficacy and safety of desmoteplase in study participants with acute ischemic stroke. It is a follow-on to the DIAS-3 study which completed in March-2014. BIOS (Brain Injury Outcomes Clinical Trial Coordinating Center) is acting as a local coordinating team for this study at Johns Hopkins.
Desmoteplase is an investigational recombinant tissue plasminogen activator (rt-PA). Early studies suggest is may have a lower bleeding risk than alteplase when given via intravenous administration in ischemic stroke. It has a broader time window (up to 9 hours) and can be given as a single bolus injection making it easier to use. The primary outcome measure is the score on the 90-day Modified Rankin Scale. The NIHSS at Day-90 is a secondary outcome measure. This therapeutic agent was initially discovered in the saliva of a vampire bat.
POINT is a randomized, double-blind, multicenter clinical trial to determine whether clopidogrel (Plavix®) is effective in preventing major ischemic vascular events such as ischemic stroke and myocardial infarction in newly-diagnosed patients with TIA and minor ischemic stroke. Study participants are enrolled within 12 hours of their symptom onset and presentation to the emergency department and are then followed for 90 days after randomization.
Johns Hopkins is participating along with up to 350 other investigational sites in partnership with the National Institute of Neurological Disorders and Stroke (NINDS) and the NETT Network. The study. which started in 2010, will enroll 5840 participants over approximately 7 years.
AVERT is a randomized multicenter clinical trial evaluating video-oculography (VOG), nystagmography and audiometry in patients presenting to an emergency department with dizziness or vertigo. The study will determine if these non-invasive tests of eye movement and hearing when combined with a structured treatment plan, resulting in a better diagnosis. More than 1 million people visit the ED each year due to dizziness. About 5% of these patients have life-threatening strokes but a third of those are misdiagnosed. It is hoped that the findings from this study will save lives and reduce costs through faster diagnosis and more appropriate treatment.
VICTAS is a randomized multicenter trial evaluating the addition of vitamin C and thiamine to glucocorticoid treatment in ICU patients with sepsis. As of Feb 2017, the trial is in early startup phase and is expected to enroll 500 patients across 20 to 30 sites over the next two years.