Clinical trial NCT05948566: Strategy for Improving Stroke Treatment Response
Official title: Strategy for Improving Stroke Treatment Response (SISTER) Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Ischemic Stroke
Lead sponsor: Translational Sciences, Inc.
Sponsor class: INDUSTRY
Collaborators: name: University of Cincinnati
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Medical University of South Carolina
name: University of Arizona
First posted: 2023-07-17
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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 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 (+/-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.

Eligibility criteria: 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:

   a. ASPECTS of 6 or more on CT (or ASPECTS of ≥7 on MRI) b. 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
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.

Primary outcomes:
measure: The proportion of patients with ANY intracerebral hemorrhage (ICH)
timeFrame: At 30 (+/- 4) hours after study drug
measure: Stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS)
timeFrame: At 30 (+/- 4) hours after study drug
Secondary outcomes:
measure: Improvement in level of global disability measured by modified Rankin Score (mRS distribution)
timeFrame: 90 (±7) days
measure: Frequency of Modified Rankin (mRS) score of 0-1 or returning to pre-stroke mRS.
timeFrame: Proportion of patients with modified Rankin scale score 0-1 or return to pre-stroke mRS at 90 (+/-7) days.
measure: NIHSS
timeFrame: 72 (±12) hours (or at discharge if sooner) after study drug administration.
measure: α2-antiplasmin (a2AP) level in plasma
timeFrame: at 3 (±1) h after completion of study drug administration
measure: Matrix metalloproteinase-9 level in plasma
timeFrame: 3 (±1) h after completion of study drug
measure: % brain tissue reperfusion
timeFrame: 30 (±4) h after study drug administration
measure: Pharmacokinetic analyses
timeFrame: at 3 (±1) h, and 30 (±4) h, 30 (±5) days, and 90 (±7) days, after completion of study drug administration.
measure: Evaluation of anti-drug antibodies
timeFrame: baseline and 90 (±7) days follow-up visit
measure: Proportion of patients with symptomatic intracerebral hemorrhage
timeFrame: 30 (±4) h of study drug administration
measure: Proportion of patients with non-intracerebral hemorrhage major or clinically relevant non-major bleeding
timeFrame: 30 days of study drug administration.
measure: Plasma fibrinogen level
timeFrame: 3 (±1) h after completion of study drug
measure: Proportion of patients with non-bleeding severe adverse events
timeFrame: 90 (±7) days
measure: Proportion of patients with stroke-related and all-cause deaths
timeFrame: 90 (±7) days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Hospital
state: Alabama
city: Phoenix
country: United States
facility: Banner University Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Phoenix
state: Arizona
city: La Jolla
country: United States
facility: UCSD Health La Jolla
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles
state: California
city: Sacramento
country: United States
facility: Sutter Medical Center
state: California
city: San Diego
country: United States
facility: UCSD Medical Center- Hillcrest Hospital
state: California
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Newark
country: United States
facility: Christiana Hospital
state: Delaware
city: Gainesville
country: United States
facility: UF Health Shands Hospital
state: Florida
city: Miami
country: United States
facility: Jackson Memorial Hospital
state: Florida
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Lexington
country: United States
facility: Baptist Healthcare System, Inc.
state: Kentucky
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Burnsville
country: United States
facility: M Health Fairview Ridges Hospital
state: Minnesota
city: Edina
country: United States
facility: M Health Fairview Southdale Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: M Health Fairview University of Minnesota Medical Center
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: Barnes Jewish Hospital
state: Missouri
city: Edison
country: United States
facility: JFK Medical Center
state: New Jersey
city: Brooklyn
country: United States
facility: NYU Langone Health
state: New York
city: Buffalo
country: United States
facility: Buffalo General Medical Center
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: Mount Sinai West
state: New York
city: New York
country: United States
facility: The Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: NYP Columbia University Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Columbus
country: United States
facility: OSU Wexner Medical Center
state: Ohio
city: Tulsa
country: United States
facility: Ascension St. John
state: Oklahoma
city: Bethlehem
country: United States
facility: Saint Luke's Hospital of Bethlehem Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina University Hospital
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Greenville Memorial
state: South Carolina
city: Memphis
country: United States
facility: Methodist University Hospital
state: Tennessee
city: Houston
country: United States
facility: Memorial Hermann Texas Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Healthcare
state: Utah
city: Charlottesville
country: United States
facility: UVA Medical Center
state: Virginia
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
Study officials:
affiliation: University of Cincinnati
name: Eva Mistry, MBBS
role: PRINCIPAL_INVESTIGATOR
References: