Research & Publications
Dr. Sheth's research focuses on the identification and translation of new therapies for patients with acute neurological injury such as stroke, brain hemorrhage, and trauma. The primary goal of his group is to identify and translate innovative approaches to improved patient care, using clinical trials in neurological disease as a platform. His group has special expertise in identifying unique patient populations (large and small) using population, genomic, and other big data, collaborating with preclinical labs to prepare pharmacotherapy for translation (including drug delivery), and advancing biomarkers and outcomes that facilitate the detection of clinically relevant treatment effect. This work is aimed primarily towards patients with all forms of cerebrovascular disease including the prevention, acute treatment, and recovery of ischemic and hemorrhagic stroke.
Specialized Terms: Brain edema; Stroke; Intracranial hemorrhage; Neurocritical Care; Critical care; Prognosis; Biomarkers; Clinical Trials
Extensive Research Description
co-Principal Investigator, “Improved Glyburide Therapy Via Acid-Triggered Release Functional Nanoparticles,” (R01NS110721-01A1) - Together with Dr. Jiangbing Zhou, we are developing novel nanoparticle formulations for treatment of acute ischemic stroke. These nanoparticle have unique structural and composition profiles tailored for acute brain injury and have been developed for a number of candidate treatments, as well as penetration and engagement across the blood-brain-barrier.
co-investigator, “Yale Site for Stroke Preclinical Assessment Network (SPAN) for Acute Neuroprotection,” UO1NS113445 - Together with Dr. Lauren Sansing, we are participating in a multi-center preclinical ischemia-reperfusion stroke model network aimed at identifying candidate therapies for stroke translation.
co-Investigator, Director of the Recruitment Core Lab, “ARCADIA-CSI (Cognition and Silent Infarcts),” U01NS110728 - Together with Dr. Maarten Lansberg at Stanford, this study will evaluate the role of silent brain infarction on functional and cognitive outcome after stroke caused by cardioembolism. It will also provide information on whether or not anticoagulation may modify this outcome.
co-Principal Investigator, “Anticoagulation in ICH Survivors for Prevention and Recovery (ASPIRE)”, NINDS, U01NS106513 - Together with Dr. Hooman Kamel at Cornell, I am leading this phase III StrokeNet clinical trial which will enroll 700 patients at 125 US centers who survive intracerebral hemorrhage and also have atrial fibrillation. The study will determine whether or not anticoagulation or aspirin results in improved stroke prevention and survival
co-Principal Investigator, “The Recovery in Stroke Using PAP: RISE-UP” Study”, NINR, RO1NR018335 - Together with Dr. Klar Yaggi, this randomized control trial, funded by the NINR, will examine whether or not sleep apnea treatment using positive airway pressure therapy can improve functional outcome and other patient centered symptoms in 180 patients. We will also obtain unique information in this population regarding adherence and qualitative benefit.
co-Principal Investigator - INTREPID (Impact of Fever Prevention in Brain Injured Patients) (Sponsor: Bard) - This is a phase III study of over 1000 ischemic and hemorrhagic stroke patients testing the following hypothesis: does fever prevention, using an advanced cooling device, result in improved neurology outcomes in patients with severe stroke.
co-Principal Investigator - Saponimod in Intracerebral Hemorrhage (Sponsor: Novartis) - This is a phase II clinical trial of S1P modulation in patients with spontaneous intracerebral hemorrhage at approximately 20 US sites. We will enroll approximately 60 patients in order to obtain information regarding the feasibility of recruitment, evaluation and administration of S1P modulators and to obtain exploratory information regarding imaging measures of swelling and inflammation and clinical outcomes.
co-Global Lead CHARM (Cirara in Large Hemishperic Infarction Analyzing mRS and Mortality) - The CHARM study is an international, multicenter, randomized, double-blind, placebo-controlled, Phase 3 study that aims to enroll 680 patients with LHI in approximately 20 countries. It will evaluate the efficacy and safety of IV glibenclamide treatment within 10 hours following stroke onset. The primary endpoint is the modified Rankin Scale (mRS), a functional outcome, assessed at 90 days. This trial represents over 10 years of a collaborative translational effort from molecular discovery at the bench to phase III trial in stroke patients who are at high risk for brain swelling.
Both the ASPIRE and RISE-UP clinical trials are both prevention and recovery clinical trials in stroke.
Neuroscience Clinical Trial Networks
I am the co-Principal Investigator of 2 NIH Networks in New England.
INFINITY (Investigations For Improved Neurological Treatments at Yale) was selected in 2018 by the National Institutes of Neurological Disorders and Stroke (NINDS) as one of approximately 25 U.S. sites designated to participate in the Network of Excellence in Neuroscience Clinical Trials (NeuroNEXT). This network conducts both biomarker validation and Phase 2 studies of treatment for neurological disease in adults and children through partnerships with academia, private foundations and industry. NeuroNEXT is designed to expand NINDS's capabilty to test the most promising new therapies; increase the efficiency of clinical trials before on embarking on larger studies; and respond quickly as new opportunities arise to test promising treatments for people with neurological disorders. INFINITY is a highly effective research team which includes both adult and pediatric neurologists, neurosurgeons, neuropsychologists, neuroradiologists, and translational scientists committed to conducting high impact clinical trials in neurological diseases.
SPIRIT (Southern New England Partnership In Stroke Research, Innovation and Treatment) was selected in 2018 by the National Institutes of Health (NIH) as one of approximately 25 U.S. Sites designed to participate in StrokeNet. The primary goal of this network is to maximize efficiencies to develop, promote and conduct high-quality, multi-site clinical trials focused on key interventions in stroke prevention, treatment and recovery. The StrokeNet Network is designed to serve as the infrastructure and pipeline for exciting new potential treatments for patients with stroke and those at risk for stroke. SPIRIT is anchored by 3 leading institutes: Yale School of Medicine, Warren Alpert School of Medicine at Brown University, and Hartford Hospital
Engineering and Technology
The nanoparticle project above is in collaboration with biomedical engineering at Yale University.
Principal Investigator, “Portable, Bedside Magnetic Resonance Imaging in Neuroscience”, Hyperfine, Inc and American Heart Association - In collaboration with Dr. W.T. Kimberly and Matthew Rosen at Harvard and with Hyperfine, we have developed and deployed the first portable, bedside MRI in the world.
Data Resources and Repository
My group works with a number of "big data" resources, including publicly available clinical trial datasets (e.g. NIH), administrative and claims datasets (e.g., Nationwide Inpatient Sample, Medicare, Healthcare Utilization Project), quality improvement (AHA-Get With the Guidelines), genomics (e.g. UK Biobank) to make and replicate clinically relevant observations and to understand current practice patterns.
co-Principal Investigator, “Intensive Blood Pressure Reduction in Deep Intracerebral Hemorrhage,” RO3NS112859 - This project examines the role of neuroanatomical location and treatment effect in prior clinical trial and observational series of patients with brain hemorrhage.
Our group fosters the development of academic investigators in clinical and translational research in brain injury from the undergraduate to the faculty level. The focus is on the themes and patient populations identified above.
Biotechnology; Brain Edema; Neurology; Neurosciences; Neurosurgery; Primary Prevention; Quality of Health Care; Subarachnoid Hemorrhage; Drug Delivery Systems; Trauma, Nervous System; Brain Hemorrhage, Traumatic; Infarction, Middle Cerebral Artery; Brain Infarction; Stroke; Biomarkers, Pharmacological; Secondary Prevention
Public Health Interests
Biomarkers; Cardiovascular Diseases; Clinical Guidelines; Clinical Trials; End-of-life Care; Ethics; Health Care Management; e-Health