The Norwegian Sonothrombolysis in Acute Stroke Study Part 2

Study Overview
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Brief Summary
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BACKGROUND: Thrombolytic drugs may dissolve blood vessel clots in acute ischemic stroke. The overall benefit of intravenous thrombolysis is substantial, but up to 2/3 of patients with large clots may not achieve re-opening of the vessel and up to 40% of the patients may remain severely disabled or die. Ultrasound accelerates clot break-up (lysis) when combined with thrombolysis (sonothrombolysis) and increases the likelihood of functional independence at 3 months. Adding intravenous ultrasound contrast (gaseous microspheres) further enhances the thrombolytic effect (contrast enhanced sonothrombolysis = CEST). Contrast enhanced ultrasound may also accelerate clot break-up in the absence of thrombolytic drugs (contrast enhanced sonolysis = CES). HYPOTHESIS: Contrast enhanced ultrasound treatment administered within 4 1/2 hours after symptom onset may be given safely to patients with acute ischemic stroke, both to those receiving intravenous thrombolysis and those not receiving intravenous thrombolysis, and will improve clinical outcome. AIMS: To compare efficacy and safety of contrast enhanced ultrasound treatment vs. no ultrasound treatment in patients with acute ischemic stroke receiving or not receiving intravenous thrombolysis. STUDY ENDPOINTS: The primary endpoints are 1) neurological improvement at 24 hours (proof of concept) and 2) excellent clinical outcome at 3 months (effect). Secondary endpoints are bleeding complications (safety), brain damage (infarct size/location) and early clinical improvement (effect).

Detailed Description
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NOR-SASS aims at testing contrast enhanced sonothrombolysis in all patients with acute ischemic stroke. Patients eligible for thrombolysis (randomized tenecteplase or alteplase) are included in the NOR-SASS A sub-study, patients receiving standard (non-trial) thrombolysis with alteplase are included in the NOR-SASS B sub-study, and patients not eligible for thrombolysis are included in the NOR-SASS C sub-study. DESIGN: NOR-SASS is a PROBE (prospective randomised, open-label, blinded endpoint) trial, designed to establish the superiority of contrast-enhanced ultrasound treatment given within 4½ hours after stroke onset in consecutively admitted patients with acute ischaemic stroke, as compared with 1) standard iv thrombolysis with tenecteplase (TNK) or alteplase (tPA) in patients eligible for thrombolytic treatment, and 2) no specific treatment in patients not eligible for thrombolytic treatment. HYPOTHESIS: 1.) In patients eligible for intravenous thrombolysis, contrast enhanced sonothrombolysis (CEST) has superior effect as compared with standard intravenous thrombolysis and may be given safely. 2.) In patients not eligible for thrombolysis, contrast enhanced sonolysis (CES) has superior effect as compared with no specific treatment and may be given safely. RANDOMISATION: In NOR-SASS-A (two step randomisation), 1st randomisation is 1:1 to either tenecteplase (TNK) or alteplase (tPA); 2nd randomisation is 1:1 to either CEST or no CEST. In NOR-SASS-B, randomisation is 1:1 to either CEST or no CEST. In NOR-SASS-C, randomisation is 1:1 to either CES or no CES.

Official Title
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Randomised Trial of Contrast-enhanced Sonothrombolysis in Acute Ischaemic Stroke

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Other: Ultrasound
* Other: Sham ultrasound


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ischemic stroke in the anterior circulation Treatment within 4.5 hours after stroke onset Informed consent Exclusion Criteria: Patients with premorbid modified Rankin Scale (mRS) score ≥3; Patients for whom a complete NIH Stroke Score cannot be obtained; Hemiplegic migraine with no arterial occlusion on baseline CT; Seizure at stroke onset and no visible occlusion on baseline CT; Intracranial haemorrhage on baseline CT; Clinical subarachnoid haemorrhage even if baseline CT is normal; Large areas of hypodense ischaemic changes on baseline CT; Patients with primary endovascular treatment; Female, pregnant or breast feeding; pericarditis; sepsis; any other serious medical illness likely to interact with treatment; confounding pre-existent neurological or psychiatric disease; unlikely to complete follow-up; any investigational drug <14 days;

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: PROBE: Prospective randomized open-label blinded-endpoint
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ultrasound<br>Patients eligible (NOR-SASS A/B) and ineligible (NOR-SASS C) for intravenous thrombolysis all receive intravenous ultrasound contrast (microbubbles). The groups are separately randomised to 2 megahertz (MHz) transcranial ultrasound treatment for one hour. | Other: Ultrasound<br>* SonoVue solution 10 ml (2 vials / 80 µl microbubbles) is given as an infusion of 0,3 ml/min for  30 minutes, using a Bracco infusion pump.<br>|
| Placebo Comparator: Sham ultrasound<br>Patients eligible (NOR-SASS A/B) and ineligible (NOR-SASS C) for intravenous thrombolysis all receive intravenous ultrasound contrast (microbubbles). The two groups are separately randomised to sham ultrasound treatment for one hour. | Other: Sham ultrasound<br>* Mounting the ultrasound headframe but connecting this to a non-operative channel<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical: Functional handicap | Sliding dichotomy/responder analysis: Excellent outcome is defined as modified Rankin Scale (mRS) 0 with baseline National Institutes of Health Stroke Scale (NIHSS), as mRS 0-1 with baseline NIHSS 8-14, as mRS 0-2 with baseline NIHSS ≥15 | 90 days | 
| Proof of concept: Early neurological improvement | NIHSS=0 or reduction of ≥4 NIHSS points compared with baseline | 22-36 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic intracerebral hemorrhage | Local or remote parenchymal haemorrhage type 2 on the 22-36 h post-treatment imaging scan, combined with a neurological deterioration of 4 points or more on the NIHSS from baseline or from the lowest NIHSS value between baseline and 24 h, or leading to death (SITS-MOST criteria). | 24-36 hours | 
| Hemorrhagic transformation | Any hemorrhagic changes (infarct or parenchymal hematoma) | 24-36 hours | 
| Short term functional outcome | Sliding dichotomy/responder analysis: Excellent outcome is defined as mRS 0 with baseline NIHSS ≤7, as mRS 0-1 with baseline NIHSS 8-14, as mRS 0-2 with baseline NIHSS ≥15 | 7 days | 
| Brain infarct size and location | MRI infarct volume and ASPECTS score | 22-36 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intervention, sonothrombolysis, Ultrasound treatment