Strategy for Improving Stroke Treatment Response

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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STRATEGY FOR IMPROVING STROKE TREATMENT RESPONSE (SISTER) TRIAL

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Biological: TS23


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Model Description: The first 50 subjects will be randomized equally to the five arms. Response Adaptive Randomization updates will occur every 50 subjects, thereafter, (favoring doses with maximum utility). For each block of 50 subjects, 13 will be allocated to control.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Biological: TS23<br>* Monoclonal antibody<br>|
| Experimental: Dose 1 TS23<br>low dose | Biological: TS23<br>* Monoclonal antibody<br>|
| Experimental: Dose 2 TS23<br>next higher dose | Biological: TS23<br>* Monoclonal antibody<br>|
| Experimental: Dose 3 TS23<br>next higher dose | Biological: TS23<br>* Monoclonal antibody<br>|
| Experimental: Dose 4 TS23<br>highest dose | Biological: TS23<br>* Monoclonal antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with ANY intracerebral hemorrhage (ICH) | Any ICH visualized on the follow-up CT scan | At 30 (+/- 6) hours after study drug | 
| Stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS) | NIHSS is a stroke severity score that ranges from 0 to 42, with higher numbers indicating a more severe stroke. The NIHSS will be adjusted for the baseline value in analysis. | At 30 (+/- 6) hours after study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in level of global disability measured by modified Rankin Score (mRS distribution) | The modified Rankin Score assessment is a 7-level disability scale that measures the degree of disability or dependence in daily activities of people who have suffered a stroke. Range 0= no disability and 6=dead. | 90 (±7) days | 
| Frequency of excellent functional outcome | Proportion of patients with modified Rankin scale score 0-1, denoting a symptom free outcome | Proportion of patients with modified Rankin scale score 0-1, denoting a symptom free outcome | 
| NIHSS | NIHSS is a stroke severity score that ranges from 0 to 42, with higher numbers indicating a more severe stroke. The NIHSS will be adjusted for the baseline value in analysis. | 72 (±12) hours (or at discharge if sooner) after study drug administration. | 
| α2-antiplasmin (a2AP) level in plasma | A serine protease inhibitor responsible for inactivating plasmin. | at 3 (±1) h after completion of study drug administration | 
| Matrix metalloproteinase-9 level in plasma | An enzyme that regulates the pathological remodeling process that involve inflammation and fibrosis associated with cardiovascular disease. | 3 (±1) h after completion of study drug | 
| % brain tissue reperfusion | Proportion of brain tissue that is reperfused on the follow-up perfusion scan compared to the baseline, calculated as: ([baseline minus follow up perfusion imaging area of hypoperfusion]/ baseline area of hypoperfusion); hypoperfusion=T max>6 seconds | 30 (±6) h after study drug administration | 
| Pharmacokinetic analyses | Measure of plasma concentrations of TS23 | at 3 (±1) h, and 30 (±4) h, 30 (±5) days, and 90 (±7) days, after completion of study drug administration. | 
| Evaluation of anti-drug antibodies | commonly used for characterization of therapeutic antibodies | baseline and 90 (±7) days follow-up visit | 
| Proportion of patients with symptomatic intracerebral hemorrhage | a blood clot large enough to cause significant neurological deterioration. | 30 (±6) h of study drug administration | 
| Proportion of patients with non-intracerebral hemorrhage major or clinically relevant non-major bleeding | major and non-major events of bleeding that is not in the brain | 30 (±5) days of study drug administration. | 
| Plasma fibrinogen level | Clotting factor | 3 (±1) h after completion of study drug | 
| Proportion of patients with non-bleeding severe adverse events | Assessment of untoward events | 90 (±7) days | 
| Proportion of patients with stroke-related and all-cause deaths | measure of important patient outcomes | 90 (±7) days |