Aureva Transcranial Ultrasound Device With tPA in Patients With Acute Ischemic Stroke

Study Overview
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Brief Summary
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This is a randomized, placebo controlled, double-blind phase 3 clinical study to evaluate the efficacy and safety of transcranial ultrasound (TUS) using the Sonolysis Headframe as an adjunctive therapy to intravenous (IV) tissue plasminogen activator (tPA) therapy in subjects with acute ischemic stroke that initially present at non-endovascular (EVT) treating hospitals that have established transport services in place to transfer subjects to hospitals capable of performing EVT.

Detailed Description
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The primary objective of this study is to assess the safety and efficacy of TUS using the Sonolysis Headframe in combination with systemic tPA (Treatment group) compared to systemic tPA alone (Control group) in subjects with acute ischemic stroke. Number of Subjects Required: Lead-in Phase: 40 subjects in the U.S.; Primary Phase: 556 total enrolled subjects (278 per arm) Number of Study Centers: Lead-in Phase: Up to 20 Institutions in U.S.; Primary Phase: Up to 70 Institutions worldwide

Official Title
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A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of the Aureva Transcranial Ultrasound Device With Tissue Plasminogen Activator in Patients With Acute Ischemic Stroke (TRUST)

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Device: tPA in combination with the Sonolysis Headframe (TUS)
* Device: tPA in combination with the Sonolysis Headframe (Sham TUS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with acute ischemic stroke Subjects that initially present at non-EVT treating hospitals that have established transport services in place to transfer subjects to hospitals capable of performing EVT Males or females 18 - 80 years of age Subjects presenting within time window for IV tPA treatment approved by local regulatory authorities but no more than 4.5 hours from onset of symptoms No signs of intracranial bleeding on assessment by non-contrast CT Subjects that in the opinion of the treating physician require treatment with full dose of IV tPA (0.9mg/kg) as standard of care per institutional standards SBP ≤ 185 mmHg and DBP ≤ 105 mmHg at baseline or after treatment of hypertension with medications prior to tPA bolus Pre-morbid mRS of 0-1 Arterial occlusion in the middle cerebral artery (MCA) M1 or proximal M2, intracranial carotid T, anterior cerebral artery (ACA) A1, basilar, proximal posterior cerebral artery (PCA) P1 or intracranial tandem lesions in these locations visible on CT angiography (CTA) Provision of informed consent as demonstrated by the subject's signature or by the signature of the subject's authorized legal representative on the Informed Consent Form in accordance with all local and national regulations and no later than 15 minutes after standard of care tPA administration Exclusion Criteria: Tandem lesions where one lesion is extracranial (carotid or vertebral artery) ASPECTS score < 6 on non contrast CT or ischemic changes that in the opinion of the investigator would be medically inappropriate for reperfusion therapy Poor collateral circulation defined as minimal or no pial collaterals in >50% of the ischemic territory Expected time between activation of Sonolysis Headframe and initiation of EVT < 90 minutes Pregnant or breast feeding women, clinical signs of pericarditis, sepsis or any other serious medical illness likely to interact with treatment, confounding preexistent neurological or psychiatric disease or test values that, in the opinion of the investigator, pose significant risk to the subject and warrant exclusion from the study Impaired renal function defined as eGFR < 60 mL/min/1.73 m2 No permanent address or phone number Any investigational drug <14 days prior to study participation Subjects with known allergy to x-ray contrast material Subjects with any standard contraindication for intravenous tPA therapy as per local or national guidelines

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Sham control and active insonation. During lead-in phase for the first 40 subjects, only active insonation will be programmed.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Control group (tPA + sham TUS)<br>Control group (tPA + sham TUS) During the primary phase of the study, subjects will be randomized 1:1 | Device: tPA in combination with the Sonolysis Headframe (Sham TUS)<br>* tPA per approved labeling Sham (inactive) TUS insonation via the Sonolysis Headframe: minimum 90 minutes - maximum 120 minutes<br>* Other names: Aureva Headframe (Sham TUS) with Tissue Plaminogen Activator (tPA);|
| Active Comparator: Treatment group (tPA + TUS)<br>Treatment group (tPA + TUS): Lead-in phase and Primary phase | Device: tPA in combination with the Sonolysis Headframe (TUS)<br>* tPA: 60 minutes per approved labeling TUS insonation via the Sonolysis Headframe: minimum 90 minutes - maximum 120 minutes<br>* Other names: Aureva Headframe (TUS) with Tissue Plaminogen Activator (tPA);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete recanalization measured by modified Arterial Occlusive Lesion (mAOL) | Complete recanalization of the primary occluded vessel as measured by the modified Arterial Occlusive Lesion (mAOL) scoring system. The mAOL assigns a score from 0 to 3, which represents the range from no recanalization to complete recanalization based on either the presence (grade 2 or 3) or absence (grades 0 or 1) of any downstream flow. | 90-120 minutes post TUS treatment before EVT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| modified Rankin Scale (mRS) score 0-2 | Functional dependence at 90 days as measured by the modified Rankin Scale (mRS). The mRS consists of 7 grades, (0-6), with 0 corresponding to no symptoms and 6 corresponding to death. For this study, functional independence will be defined as those subjects that achieve a mRS score of 0-2 at 90 days. | 90 days +/- 10 days | 
| Neurologic Status at 24 hours post treatment measured by National Institute of Health's Stroke Scale (NIHSS). | NIHSS has 15 items. Ratings for each item are scored on a 0-3 to 0-5 scale, with a total score of 0 for normal and 42 for maximally impaired. | 24 hours post TUS treatment | 
| Partial or complete recanalization as measured by mAOL score of 2-3. | See description in Primary Outcome Measure. | 90-120 minutes post TUS treatment before EVT | 
| Partial or complete recanalization as measured by Thrombolysis In Cerebral Ischemia (TICI) score of 2-3 | TICI Scale: [0] - No antegrade flow beyond the point of occlusion. [1] - The contrast material passes beyond the area of obstruction but fails to opacify the entire cerebral bed distal to the obstruction. [2] - The contrast material passes beyond the obstruction and opacifies the arterial bed distal to the obstruction. However, the rate of entry of contrast into the vessel distal to the obstruction and/or its rate of clearance from the distal bed are perceptibly slower than its entry into and/or clearance from comparable areas not perfused by the previously occluded vessel. [3] - Antegrade flow into the bed distal to the obstruction occurs as promptly as into the obstruction and clearance of contrast material from the involved bed is as rapid as from an uninvolved other bed of the same vessel or the opposite cerebral artery. | 90-120 minutes post TUS treatment before EVT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke, Acute Stroke