Overview
SISTER is a Phase-II, prospective, randomized, placebo-controlled, blinded, dose finding trial that aims to determine the safety and preliminary efficacy of TS23, a monoclonal antibody against the alpha-2 antiplasmin (a2-AP), in acute ischemic stroke.
Description
SISTER is a Phase II, Bayesian, adaptive, randomized, dose-finding trial of TS23 in patients with acute ischemic stroke. Patients with an anterior cerebral circulation acute ischemic stroke and present between 4.5 to 24 hours of their last known well with a presenting NIH Stroke Scale Score >/=6 and an imaging evidence of salvageable brain tissue will be eligible and will be approached for an informed consent for study participation. After informed consent is provided, the study will randomize to 4 doses of TS23 and placebo. The trial will enroll 300 subjects at up to 50 participating sites.
The effects of TS23 will be evaluated on two following primary outcomes using a utility function: 1) primary safety outcome: any intracerebral hemorrhage at 30 (+/-6) hours and 2) primary efficacy outcome: NIH Stroke Scale score at 30 (+/-6) hours after drug administration. The study will follow participants for 90 (+/-7) days.
Primary Objective: To identify a dose of TS23 that is safe and more efficacious than placebo for the treatment of patients from 4.5 to 24 hours of last known well, who have evidence of core-penumbra mismatch on perfusion imaging and are not a candidate for standard of care reperfusion therapies.
Eligibility
Inclusion Criteria:
- Age 18 years and older
- Suspected anterior circulation acute ischemic stroke
- Presenting NIH Stroke Scale score >/= 6
- Favorable baseline neuroimaging
- CT scan with ASPECTS of >/=6, or MRI with ASPECTS of >/=7 and
- CT or MR Perfusion with a mismatch ratio >1.2 between the volume of hypoperfusion and the volume of the ischemic core, an absolute difference in volume > 10 ml, and an ischemic-core volume of less than 70 ml. and
- Able to receive assigned study drug within 4.5 to 24 hours of stroke onset or last known well
- Informed consent for the study participation obtained from participant or their
legally authorized representatives.
Exclusion Criteria:
- Patients planned to receive endovascular treatment.
- Patients that received or planned to receive intravenous thrombolysis.
- Pre-stroke modified Rankin score >2.
- Known previous allergy to antibody therapy.
- Known pregnancy or positive urine or serum pregnancy test for women of child bearing potential.
- Known previous stroke in the past 90 days.
- Known previous intracranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arterial venous malformation.
- Clinical presentation suggestive of a subarachnoid hemorrhage, even if initial CT scan was normal.
- Surgery or biopsy of parenchymal organ in the past 30 days.
- Known trauma with internal injuries or ulcerative wounds in the past 30 days.
- Severe head trauma in the past 90 days.
- Persistent systolic blood pressure >180mmHg or diastolic blood pressure >105mmHg despite best medical management.
- Serious systemic hemorrhage in the past 30 days.
- Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR >1.7.
- Platelets <100,000/mm3.
- Hematocrit <25 %.
- Elevated PTT above laboratory upper limit of normal.
- Creatinine > 4 mg/dl, or patients receiving renal dialysis, regardless of creatinine.
- Received heparin or low molecular weight heparins (such as dalteparin, enoxaparin, tinzaparin) in full dose within the previous 24 hours.
- Received Factor Xa inhibitors (such as fondaparinux, apixaban or rivaroxaban) within the past 48 hours.
- Received direct thrombin inhibitors (e.g., argatroban, dabigatran, bivalirudin, desirudin, lepirudin) within 48 hours.
- Received glycoprotein IIb/IIIa inhibitors within the past 14 days.
- Known pre-existing neurological or psychiatric disease which would confound the neurological/functional evaluations.
- Current participation in another research drug treatment protocol (i.e., participants could not start another experimental agent until after 90 days).
- Concurrent acute myocardial infarction, pulmonary embolism, deep venous thrombosis or other thrombotic event that requires anticoagulation or anti-platelet treatment.