Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy

Study Overview
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Brief Summary
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This clinical trial will enroll 110 patients from approximately 15 Canadian stroke centres. Patients coming to the emergency department with bleeding in the brain not due to trauma or other known causes who can be treated within 6 hours of onset will undergo CT angiography using standard CT scanners (CAT scan). Those with a spot sign, a type of marker on the CT scan that shows the brain is still bleeding, will be randomly assigned to a single injection of factor 7(a blood clotting drug used in hemophilia) or placebo (inactive saline); patients without a spot sign will not be treated. The researchers will look at how much bleeding happens after the treatments are administered, as well as clinical outcomes such as death and disability. The researchers think that factor 7 will cause the bleeding to stop faster and possibly decrease death and disability.

Detailed Description
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This phase II double blind RCT will enroll 110 patients from approximately 15 Canadian stroke centres. Acute ICH patients who can be treated within 6 hours of onset will undergo CT angiography using standard CT procedures. Those with a spot sign will be randomly assigned in a 1:1 ratio to a single injection of rFVIIa 80 µg/kg or placebo; patients without a spot sign will not be treated. The primary endpoint is ICH expansion within 24 hours.

Official Title
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Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy: SPOTLIGHT

Conditions
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Stroke

Intervention / Treatment
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* Biological: rfVIIa
* Other: Standard saline solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Acute spontaneous primary supratentorial ICH diagnosed by CT scan. Presence of a spot sign within the hematoma on CTA source images Baseline ICH volume 3-90 ml Age 18 or older Investigator is able to randomize and administer study drug as soon as possible within a target of 60 minutes after CT angiogram and no later than 6 hours after stroke symptom onset (using the last seen normal principle). Plan to provide full medical care for at least 24 hours Assent-consent from patient or LAR prior to enrolment, or a waiver of consent (where REB approved) if patient/LAR assent-consent is not possible prior to enrolment. Exclusion Criteria Brainstem or cerebellar hemorrhage. ICH secondary to known or suspected trauma, aneurysm, vascular malformation, hemorrhagic conversion of ischemic stroke, venous sinus thrombosis, thrombolytic treatment, tumour, or infection; or an in-hospital ICH or ICH as a result of any in-hospital procedure or illness. Baseline brain imaging shows evidence of acute or subacute ischemic stroke (chronic infarcts are not an exclusion). Contrast administration within the previous 24 hours. Evidence of thromboembolic risk factors, defined as any of the following: known history within the past 6 months of any of the following: (a) myocardial infarction, (b) coronary artery bypass surgery, (c) angina, (d) ischemic stroke, (e) transient ischemic attack, (f) carotid endarterectomy, (g) cerebral bypass surgery, (h) deep venous thrombosis, (i) pulmonary embolism, (j) any vascular angioplasty, stenting (coronary, peripheral vascular or cerebrovascular) or filter (e.g. vena cava filter);(k) prosthetic cardiac valve; and/or (l) known history of a high-risk thrombophilia (e.g. antithrombin III deficiency, antiphospholipid antibody syndrome, protein C deficiency, etc.) Known hereditary (e.g. hemophilia) or acquired hemorrhagic diathesis or coagulation factor deficiency. Any condition known that the investigator feels would pose a significant hazard if rFVIIa were administered. Planned surgery for ICH within 24 hours (placement of intraventricular catheter is not an exclusion). Planned withdrawal of care before 24 hours post-ICH onset. Known participation in another therapeutic trial. Known allergy or other contraindication to iodinated contrast dye. Known or suspected hypersensitivity to the trial product. Known unfractionated heparin use - must check PTT and exclude if elevated above upper limit of local lab's reference range. Known low-molecular weight heparin, heparinoid, factor X inhibitor, or direct thrombin inhibitor use within previous 7 days. Known GPIIb/IIIa antagonist use in previous 2 weeks. Known warfarin (or other anticoagulant) therapy with INR >1.40. Note: if the patient is suspected to have cirrhosis, study staff are to wait for the INR value prior to dosing, and ensure not to enroll the patient if the INR value is >1.40. Otherwise the physician should use their discretion if they believe the patient is not at risk for elevated INR. Concurrent or planned treatment with prothrombin complex concentrate, vitamin K, fresh frozen plasma, or platelet transfusion. Pregnancy or lactation. Women of childbearing potential must have a negative pregnancy test prior to randomization. Current clinical symptoms suggestive of acute coronary ischemia (e.g. chest pain). Baseline ECG evidence of acute coronary ischemia (e.g. ST elevation in 2 contiguous leads, new LBBB, ST depression). Baseline platelet count <50,000 or INR >1.40 or elevated PTT

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Niastase RT<br>Niastase RT 80ug/kg IV bolus | Biological: rfVIIa<br>* 80ug/kg IV bolus<br>* Other names: Niastase RT;|
| Placebo Comparator: Placebo<br>saline IV bolus | Other: Standard saline solution<br>* Saline<br>* Other names: Saline solution sourced from local hospital;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICH size | Difference between groups in ICH size on CT scan at 24 hours post-dose, adjusted for baseline ICH size | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility | Percentage of sites who can meet recruitment targets of 2 patients per site per year; % patients who meet the target time of <45 minutes from emergency department arrival to the start of the scan; % patients who meet the target time of <60 minutes from the end of the CT angiogram to administration of study drug; Local site spot sign interpretation accuracy as judged by central adjudicator; protocol violations | 0 | 
| Waiver of consent process evaluation/effectiveness | Waiver of consent use, acceptability, and effect on treatment times. Questionnaire will be administed to subject/LAR at 4 days and 90 days. | 4,90 days | 
| Acute blood pressure control | % subjects where blood pressure control was acheived, defined as achieving systolic BP <180 mmHg within 1 hour post-randomization | 1hr | 
| Thromboembolic events | Incidence of myocardial infarction and ischemic stroke within 4 days; any other arterial or venous thromboembolic SAEs within 4 days | 4 days | 
| Mortality | 90-day mortality rate | 90 days | 
| Unstable angina | Unstable angina w/in 4 days of treatment | 4 days | 
| Troponin increase | Troponin rise above upper limit of normal within 4 days (without clinical symptoms or ECG evidence of acute coronary syndrome) | 4 days | 
| DVT | Deep venous thrombosis (DVT) within 4 days | 4 days | 
| Pulmonary embolism | PE within 30 days | 30 days | 
| Cognition | Montreal Cognitive Assessment (MoCA) and Stroke Impact Scale at 90 days and 1 year. | 90 days, 1 year | 
| Disability | Proportion of subjects with modified Rankin score 5-6 (death or severe disability) at 90 days and 1 year | 90 d, 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke, ICH, Intracerebral hemorrhage, acute stroke, rfVIIa, Niastase