UG3NS125023

Strategy for Improving Stroke Treatment Response (SISTER) Trial - The Introduction of Recombinant Tissue Plasminogen Activators (R-TPA, Alteplase) 25 years ago, and the recent development of endovascular therapy (EVT), significantly reduced neurologic disability in patients with ischemic stroke. Still, only 20% of stroke patients in the US are eligible for these therapies and 70% of those treated are left disabled. Unfortunately, these therapies are also associated with toxic effects such as brain hemorrhage.

For many patients, such as those who would be treated at 4.5-24 hours after stroke without large vessel occlusion, no established therapy exists. We urgently need to develop safer and more effective treatments that can lessen the suffering and enormous costs of disability after ischemic stroke.

NINDS-funded research shows that A2-antiplasmin (A2AP) is a molecule that plays a crucial, deleterious role in acute ischemic stroke. High A2AP levels are linked to an increased risk of R-TPA failure clinically, and A2AP increases brain injury in a dose-dependent fashion in preclinical models. A2AP blocks thrombus dissolution initiated by R-TPA and increases microvascular thrombosis. A2AP promotes neutrophil recruitment and matrix metalloproteinase-9 (MMP-9) expression, which enhances blood-brain barrier breakdown to cause intracranial hemorrhage.

Conversely, A2AP deficiency, or a monoclonal antibody that inactivates A2AP (A2AP-I), profoundly reduces apoptosis, MMP-9 expression, microvascular thrombosis, hemorrhage, and swelling by comparison to R-TPA or no treatment. Importantly, an A2AP-I has a several-fold longer therapeutic window than R-TPA. Compared to R-TPA, an A2AP-I significantly decreases brain infarction, brain hemorrhage, disability, and mortality in preclinical stroke. Robust studies from multiple labs, using different models and tools, show consistent effects. Taken together, these data suggest that an A2AP-I alone has extraordinary potential for safe treatment of human ischemic stroke, particularly in an extended ischemic time window.

The monoclonal antibody A2AP-I, TS23, was developed with NIH/NINDS research support. In a Phase I trial of healthy volunteers, TS23 induced dose-related A2AP inactivation, amplified endogenous thrombus dissolution, and was well-tolerated. A randomized, placebo-controlled, blinded, Bayesian, dose-finding, Phase II SISTER trial within the NIH StrokeNet will test the central hypothesis that, when compared to standard medical care, TS23 will safely improve neurological outcomes in patients with extended ischemia, without completed infarction.

TS23 will be compared to placebo in 300 acute ischemic stroke patients presenting 4.5-24 hours after symptom onset with favorable perfusion imaging. If TS23 proves to be safe and potentially efficacious, based on reduction of neurological impairment, a future, pivotal clinical trial will be planned.

University Of Cincinnati

NOT APPLICABLE

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Cincinnati, Ohio 452210222 United States

Single Zip Code

NIH StrokeNet Clinical Trials and Biomarker Studies for Stroke Treatment, Recovery, and Prevention (UG3/UH3 Clinical Trial Optional) (PAR-20-285)

Amendment Since initial award the End Date has been shortened from 06/30/28 to 06/30/24.