Ischemic Stroke
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALTS23
Monoclonal antibody
Sponsors
Translational Sciences, Inc.
University of Cincinnati
National Institute of Neurological Disorders and Stroke (NINDS)
Medical University of South Carolina
University of Arizona
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 18 years and older 2. Suspected anterior circulation acute ischemic stroke 3. NIH Stroke Scale score ≥4 prior to randomization a. The participant must have a clearly disabling deficit if NIHSS is 4-5. 4. Favorable baseline neuroimaging consisting of all of the following: 1. ASPECTS of 6 or more on CT (or ASPECTS of ≥7 on MRI) 2. 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%). 5. Able to receive assigned study drug within 4.5 to 24 hours of stroke onset or last known well. 6. Able to receive assigned study drug within 120 minutes of qualifying perfusion imaging. \* 7. 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.
Exclusion criteria
1. Received endovascular treatment with clot engagement. 1. 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. 2. Patients who undergo groin puncture but clot is not engaged due to reasons other than spontaneous distal migration are NOT permitted. 2. Received or planned to receive intravenous thrombolysis. 3. Pre-stroke modified Rankin score \>2. 4. Previous treatment with TS23 or known previous allergy to antibody therapy. 5. 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. 6. Known previous stroke in the past 90 days. 7. Known previous intracranial hemorrhage, intracranial neoplasm, subarachnoid hemorrhage, or arterial venous malformation. 8. Known active diagnosis of intracranial neoplasm. 9. Clinical presentation suggestive of a subarachnoid hemorrhage, even if initial CT scan was normal. 10. Surgery or biopsy of parenchymal organ in the past 30 days. 11. Known trauma with internal injuries or persistent ulcerative wounds in the past 30 days. 12. Severe head trauma in the past 90 days. 13. Persistent systolic blood pressure \>180mmHg or diastolic blood pressure \>105mmHg despite best medical management. 14. Serious systemic hemorrhage in the past 30 days. 15. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with International Normalized Ratio (INR) \>1.7. 16. Platelets \<100,000/mm3. 17. Hematocrit \<25 %. 18. Elevated aPTT above laboratory upper limit of normal. 19. Creatinine \> 4 mg/dl, or patients receiving renal dialysis, regardless of creatinine. 20. Received the following within the previous 24 hours: 1. If patient received unfractionated heparin within the last 24 hours, the patient must have an aPTT within normal range prior to enrollment. 2. Low molecular weight heparins such as Dalteparin, enoxaparin, tinzaparin in full dose within the previous 24 hours. 21. Received Factor Xa inhibitors (such as Fondaparinux, apixaban or rivaroxaban) within the past 48 hours. 22. Received direct thrombin inhibitors (e.g., argatroban, dabigatran, bivalirudin, desirudin, lepirudin) within 48 hours. 23. Received glycoprotein IIb/IIIa inhibitors within the past 14 days. 24. Known pre-existing neurological or psychiatric disease which would confound the neurological/functional evaluations. 25. Current participation in another research drug treatment protocol (i.e., participants could not start another experimental agent until after 90 days). 26. Concurrent acute myocardial infarction, pulmonary embolism, deep venous thrombosis or other thrombotic event that requires anticoagulation or anti-platelet treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The proportion of patients with ANY intracerebral hemorrhage (ICH) | At 30 (+/- 4) hours after study drug | Any ICH visualized on the follow-up CT scan |
| Stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS) | At 30 (+/- 4) hours after study drug | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in level of global disability measured by modified Rankin Score (mRS distribution) | 90 (±7) days | 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. |
| Frequency of Modified Rankin (mRS) score of 0-1 or returning to pre-stroke mRS. | Proportion of patients with modified Rankin scale score 0-1 or return to pre-stroke mRS at 90 (+/-7) days. | Proportion of patients with modified Rankin scale score 0-1 or return to pre-stroke mRS. |
| NIHSS | 72 (±12) hours (or at discharge if sooner) after study drug administration. | 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. |
| α2-antiplasmin (a2AP) level in plasma | at 3 (±1) h after completion of study drug administration | A serine protease inhibitor responsible for inactivating plasmin. |
| Matrix metalloproteinase-9 level in plasma | 3 (±1) h after completion of study drug | An enzyme that regulates the pathological remodeling process that involve inflammation and fibrosis associated with cardiovascular disease. |
| % brain tissue reperfusion | 30 (±4) h after study drug administration | 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 |
| Pharmacokinetic analyses | 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. | Measure of plasma concentrations of TS23 |
| Evaluation of anti-drug antibodies | will be measured at baseline and 90 (±7) days follow-up visit for approximately 50 mITT participants. | commonly used for characterization of therapeutic antibodies |
| Proportion of patients with symptomatic intracerebral hemorrhage | 30 (±4) h of study drug administration | a blood clot large enough to cause significant neurological deterioration. |
| Proportion of patients with non-intracerebral hemorrhage major or clinically relevant non-major bleeding | 30 days of study drug administration. | major and non-major events of bleeding that is not in the brain |
| Plasma fibrinogen level | 3 (±1) h after completion of study drug | Clotting factor |
| Proportion of patients with non-bleeding severe adverse events | 90 (±7) days | Assessment of untoward events |
| Proportion of patients with stroke-related and all-cause deaths | 90 (±7) days | measure of important patient outcomes |
Countries
United States
Contacts
CONTACTRebeca Aragon Garcia, BS, CCRC
CONTACTPam Plummer, MSN,RN, CCRC
PRINCIPAL_INVESTIGATOREva Mistry, MBBS
University of Cincinnati
Outcome results
None listed