Phase 3, Randomized, Placebo-Controlled, Double-Blinded Trial of the Combined Lysis of Thrombus With Ultrasound and Systemic Tissue Plasminogen Activator (tPA) for Emergent Revascularization in Acute Ischemic Stroke

Study Overview
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Brief Summary
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This is a randomized, placebo-controlled, phase 3 clinical trial to evaluate the efficacy and safety of transcranial ultrasound (US) as an adjunctive therapy to tissue plasminogen activator (tPA) treatment in subjects with acute ischemic stroke.

Detailed Description
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The primary objective of this trial is to provide information regarding the efficacy of a combined treatment with transcranial US and systemic tPA (Target group) compared to systemic tPA alone (Control group) in subjects with acute ischemic stroke. The primary efficacy endpoint is functional outcome at 3 months from stroke onset (modified Rankin Score ordinal shift analysis). The primary safety endpoint is the proportion of subjects in the Target vs Control group experiencing symptomatic intracranial hemorrhage (sICH) within 24 hours of treatment.

Official Title
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A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of the Combined Lysis of Thrombus With Ultrasound and Systemic Tissue Plasminogen Activator (tPA) for Emergent Revascularization (CLOTBUST-ER) in Acute Ischemic Stroke

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Device: Transcranial ultrasound as an adjunctive therapy to tPA
* Drug: Standard of care tPA therapy for acute ischemic stroke


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females 18 - 80 years of age Subjects presenting within timeframe for intravenous 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 with neurological deficits of a total NIHSS score ≥ 10 points Subjects that in the opinion of the treating physician require treatment with full dose IV tPA 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 modified Rankin score of 0-1 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 Co-signature on the Informed Consent Form by a qualified member of the study staff signifying that, in his/her professional opinion, informed consent has been obtained in accordance with all local and national regulations For subjects in the optional arterial recanalization substudy: Occlusion located in the intracranial carotid tee through mid M2 or proximal A2, or intracranial vertebrobasilar or P1/proximal P2 segments or tandem lesions Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min for patients undergoing CTA or MRA Exclusion Criteria: Subjects with primary intra-arterial thrombolysis Females who are pregnant or breast feeding Subjects receiving other investigational drugs, procedures, or therapies within 30 days prior to study treatment Subjects with any standard contraindication for intravenous tPA therapy Significant concurrent medical/neurological conditions or test values that, in the opinion of the investigator, pose significant risk to the subject and warrant exclusion from the study

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Target group<br>A combined treatment with transcranial US and systemic tPA | Device: Transcranial ultrasound as an adjunctive therapy to tPA<br>* tPA per approved labeling administered over 60 minutes Ultrasonic headframe with active insonation for 120 minutes<br>|
| Active Comparator: Control group<br>Systemic tPA alone | Drug: Standard of care tPA therapy for acute ischemic stroke<br>* tPA per approved labeling administered over 60 minutes Ultrasonic headframe with sham (inactive) insonation for 120 minutes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin score ordinal shift analysis | The primary objective of this study is to compare clinical recovery rates (modified Rankin score ordinal shift analysis) at 3 months after stroke onset. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic intracerebral hemorrhage | The secondary outcome is a comparison of the rates of symptomatic intracerebral hemorrhage within 0-24 hours from initiation of treatment. | 0-24 hours from treatment |