Strategy for Improving Stroke Treatment Response

Официальное название

Strategy for Improving Stroke Treatment Response (SISTER) Trial

Обзор

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.

Подробное описание

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 \>/=4 (with the patient having a clearly disabling deficit if the NIHSS is 4 or 5) 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 up to 300 subjects at up to 60 participating US sites and up to 17 Canadian 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 (+/-4) hours and 2) primary efficacy outcome: NIH Stroke Scale score at 30 (+/-4) 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.

Вмешательства

• Биопрепарат TS23
  Monoclonal antibody

Первичные конечные точки

• The proportion of patients with ANY intracerebral hemorrhage (ICH) [Срок оценки: At 30 (+/- 4) hours after study drug]
• Stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS) [Срок оценки: At 30 (+/- 4) hours after study drug]

Вторичные конечные точки (12)

• Improvement in level of global disability measured by modified Rankin Score (mRS distribution) [Срок оценки: 90 (±7) days]
• Frequency of Modified Rankin (mRS) score of 0-1 or returning to pre-stroke mRS. [Срок оценки: Proportion of patients with modified Rankin scale score 0-1 or return to pre-stroke mRS at 90 (+/-7) days.]
• NIHSS [Срок оценки: 72 (±12) hours (or at discharge if sooner) after study drug administration.]
• α2-antiplasmin (a2AP) level in plasma [Срок оценки: at 3 (±1) h after completion of study drug administration]
• Matrix metalloproteinase-9 level in plasma [Срок оценки: 3 (±1) h after completion of study drug]
• % brain tissue reperfusion [Срок оценки: 30 (±4) h after study drug administration]
• Pharmacokinetic analyses [Срок оценки: 3 (±1) h, 30 (±4) h, 30 (±5) days & 90 (±7) days after study drug administration. At 90 (±7) days for approximately 50 mITT participants. After approximately 50 mITT participants, it will be obtained at 72h(+12 hrs)/discharge visit, whichever comes 1st.]
• Evaluation of anti-drug antibodies [Срок оценки: will be measured at baseline and 90 (±7) days follow-up visit for approximately 50 mITT participants.]
• Proportion of patients with symptomatic intracerebral hemorrhage [Срок оценки: 30 (±4) h of study drug administration]
• Proportion of patients with non-intracerebral hemorrhage major or clinically relevant non-major bleeding [Срок оценки: 30 days of study drug administration.]
• Plasma fibrinogen level [Срок оценки: 3 (±1) h after completion of study drug]
• Proportion of patients with non-bleeding severe adverse events [Срок оценки: 90 (±7) days]

Критерии участия

Критерии включения

• Age 18 years and older
• Suspected anterior circulation acute ischemic stroke
• NIH Stroke Scale score ≥4 prior to randomization

a. The participant must have a clearly disabling deficit if NIHSS is 4-5.

• Favorable baseline neuroimaging consisting of all of the following:

• ASPECTS of 6 or more on CT (or ASPECTS of ≥7 on MRI)
• Favorable perfusion imaging on CT perfusion (CTP)/MR-perfusion weighted imaging (PWI) consisting of all of the following:

i. Mismatch ratio of penumbra: core >1.2 ii. Mismatch volume >10 cc iii. Core <70 cc

c. If CT hypodensity is present, then in the investigator's visual assessment, the total acute infarct volume combined area of (a) the CT hypodensity and (b) the perfusion-based core volume (CBF<30%) should be smaller than perfusion-based volume (area of Tmax>6s minus CBF<30%).

• Able to receive assigned study drug within 4.5 to 24 hours of stroke onset or last known well.
• Able to receive assigned study drug within 120 minutes of qualifying perfusion imaging. \*
• Informed consent for the study participation obtained from participant or their legally authorized representatives.

• Study drug administration is encouraged within 90 minutes after qualifying perfusion image but is allowed up to 120 minutes. After 120 minutes, another perfusion image to ensure that inclusion criteria are met is required.

Критерии исключения

• Received endovascular treatment with clot engagement.

• Patients who undergo groin puncture but clot engagement is not attempted due to spontaneous distal migration are permitted to be enrolled in the trial if all other eligibility criteria are met.
• Patients who undergo groin puncture but clot is not engaged due to reasons other than spontaneous distal migration are NOT permitted.
• Received or planned to receive intravenous thrombolysis.
• Pre-stroke modified Rankin score >2.
• Previous treatment with TS23 or known previous allergy to antibody therapy.
• Known pregnancy, women who are breastfeeding or plan to breastfeed within 3 months of receiving TS23 or have a positive urine or serum pregnancy test for women of childbearing potential.
• Known previous stroke in the past 90 days.
• Known previous intracranial hemorrhage, intracranial neoplasm, subarachnoid hemorrhage, or arterial venous malformation.
• Known active diagnosis of intracranial neoplasm.
• 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 persistent 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 International Normalized Ratio (INR) >1.7.
• Platelets <100,000/mm3.
• Hematocrit <25 %.
• Elevated aPTT above laboratory upper limit of normal.
• Creatinine > 4 mg/dl, or patients receiving renal dialysis, regardless of creatinine.
• Received the following within the previous 24 hours:

• If patient received unfractionated heparin within the last 24 hours, the patient must have an aPTT within normal range prior to enrollment.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

США · 52 центра

• University of Alabama Hospital — Birmingham
• Banner University Medical Center — Phoenix
• Mayo Clinic Phoenix — Phoenix
• Banner University Medical Center - Tucson — Tucson
• UCSD Health La Jolla — La Jolla
• Kaiser Permanente Los Angeles — Los Angeles
• Sutter Medical Center — Sacramento
• UCSD Medical Center- Hillcrest Hospital — San Diego
• … и ещё 44 центра

Идентификаторы

NCT: NCT05948566 · TS23-U202 · UH3NS125023

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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