In this Partners SPOTRIAS renewal application, we propose three highly innovative stroke studies. Two are clinical trials, a phase II safety study to expand the use of tPA to patients lacking a clear stroke onset time using the MRI signature to predict time of onset, and a translational study which culminates in a Phase 1B trial of a novel therapeutic approach, ROCK inhibition with SLx-2119. Both studies build upon translational preclinical and imaging studies performed at the MGH and BWH. The third project is an fMRI recovery project, which is being performed in collaboration with Columbia University. These unique projects seek to expand the use of acute stroke therapies and improve prediction of outcome. We have applied to renew the four requisite Cores, and an optional Neuroimaging Core from our first SPOTRIAS cycle. The Access and Administrative Core (Core A) leverages the considerable clinical resources at Partners to treat acute stroke patients with thrombolytic therapy as rapidly as possible, and enroll subjects in SPOTRIAS projects. The Neuroimaging Core (Core B) has established mechanisms for standardized imaging data retrieval, analysis, and archiving. The Blood and Tissue Core (Core C) will support blood sample collection and processing for Project 2 and SPOTRIAS plasma repository sample submission. The Biostatistics and Data Management Core (Core D) will continue to provide state-of-the- art support for the SPOTRIAS projects to ensure high quality data and statistical analyses. In addition, we have added a new, discrete Training Core (Core E) as part of this submission. This new Core will strengthen the integration between the clinical and research acute stroke fellowships and coordinate the training experience for the SPOTRIAS fellows.

Public Health Relevance

Stroke poses a major health burden on the population of the United States. With only one approved acute stroke therapy (intravenous tPA), and limited use of that treatment, there is a dire need for additional translational research to develop new therapeutic approaches and novel paradigms for the delivery of acute stroke care. 2P50NS051343-06/Project 1 Schwamm, Lee DESCRIPTION (provided by applicant): Despite significant progress in stroke prevention and its acute treatment, stroke remains the third leading cause of death and a leading cause of adult morbidity worldwide. By defining "stroke symptom onset" in the most conservative manner, namely the time the patient was last seen well, many patients whose onset is unwitnessed are automatically ineligible for thrombolytic therapy even if their true time of onset would allow them to qualify. If a technique existed that could replace the human witness and testify that the stroke was in fact less than 3.5 hours duration, then these patients could be considered for alteplase treatment under current American Heart Association (AHA) guidelines, and be treated if eligible according to the inclusion and exclusion criteria. Many stroke patients are rapidly brought to the hospital within 3 hours of the time of symptom discovery, but FDA indications exclude them from consideration for intravenous alteplase if it has been greater than 3 hours since the time they were last known to be well. We propose to use advanced MR imaging as the "witness" to testify as to stroke duration in those patients who do not have a human witness in an open label Phase Ha safety study of thrombolysis in these patients. We have modeled the other eligibility criteria after the ECASS3 trial design and the current AHA guidelines in order to limit the variable of interest to the use of MR as the determinant of time of stroke onset. We will exclude patients from the study who arrive within 3 hours from last seen well since these patients are eligible for on-label treatment with thrombolysis. Because the study is open-label and investigators are unblinded, we will use the more conservative ECASS-2 definition of symptomatic ICH. This is defined as any hemorrhage with neurologic deterioration, as indicated by an NIHSS score that was higher by 4 points or more than the value at baseline or the lowest value in the first 7 days or any hemorrhage leading to death, and does not require that the ICH be classified as causally linked to the neurologic deterioration. If our study is successful, we can potentially expand use of lytics to a stroke patient population for whom little acute intervention is currently offered.

Public Health Relevance

Stroke is a leading cause of death and morbidity in the US. Thrombolysis is approved by the FDA for treatment within 180 minutes from when a patient was last seen well. Approximately 25% of stroke patients have unwitnessed onset times. This study seeks to expand IV thrombolysis to these patients using neuroimaging as the "witness" to establish the stroke duration when a human witness is unavailable.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1-SRB-R (46))
Program Officer
Janis, Scott
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Matsouaka, Roland A; Betensky, Rebecca A (2015) Power and sample size calculations for the Wilcoxon-Mann-Whitney test in the presence of death-censored observations. Stat Med 34:406-31
Brouwers, H Bart; Raffeld, Miriam R; van Nieuwenhuizen, Koen M et al. (2014) CT angiography spot sign in intracerebral hemorrhage predicts active bleeding during surgery. Neurology 83:883-9
Brouwers, H Bart; Chang, Yuchiao; Falcone, Guido J et al. (2014) Predicting hematoma expansion after primary intracerebral hemorrhage. JAMA Neurol 71:158-64
Radmanesh, Farid; Devan, William J; Anderson, Christopher D et al. (2014) Accuracy of imputation to infer unobserved APOE epsilon alleles in genome-wide genotyping data. Eur J Hum Genet 22:1239-42
Boulouis, Grégoire; Dumas, Andrew; Betensky, Rebecca A et al. (2014) Anatomic pattern of intracerebral hemorrhage expansion: relation to CT angiography spot sign and hematoma center. Stroke 45:1154-6
Kimberly, W Taylor; Battey, Thomas W K; Pham, Ly et al. (2014) Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocrit Care 20:193-201
Ruff, Ilana M; Ali, Syed F; Goldstein, Joshua N et al. (2014) Improving door-to-needle times: a single center validation of the target stroke hypothesis. Stroke 45:504-8
Boltze, Johannes; Ayata, Cenk; Wagner, Daniel-Christoph et al. (2014) Preclinical phase III trials in translational stroke research: call for collective design of framework and guidelines. Stroke 45:357
Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey et al. (2014) Amyloid and APOE ?4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology 82:1760-7
Opherk, Christian; Gonik, Mariya; Duering, Marco et al. (2014) Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL. Stroke 45:968-72

Showing the most recent 10 out of 73 publications