CLOTBUST Hands-Free: A Phase I/II Pilot Safety Trial "CLOTBUST-HF"

Completed

Phase 1/2 Results

Trial Description

The purpose of CLOTBUST-HF is to determine the safety of a novel, external Hands-Free transcranial Doppler (TCD) ultrasound system in healthy volunteers and ischemic stroke patients. If found to be safe, the widespread use of operator-independent, ultrasound-enhanced thrombolysis will allow the planning for a large Phase III efficacy trial.

Detailed Description

Ultrasound energy to enhance intravenous rt-PA thrombolysis is a promising novel treatment modality for ischemic stroke. Despite encouraging safety data utilizing diagnostic frequencies of transcranial Doppler (TCD) ultrasound, lack of widespread availability of trained personnel has limited its application.
- The primary specific aim for this pilot phase I/II study is to assess the safety of a novel, external Hands-Free TCD ultrasound system. Safety of the new Hands-Free TCD system will first be assessed in healthy volunteers. Safety in these participants will be determined by detailed neurological and dermatological exams and MRI imaging of the brain. Next, safety of the device will be evaluated in two distinct sets of acute ischemic stroke patients: 0-3 hour patients treated with standard IV rt-PA and 3-6 hour non-lytic, image-selected patients treated with sonolysis (with or without intravenous microbubbles). Among the healthy volunteers the primary measures of safety will be to have no detectable changes in a detailed neurological exam nor any blood- brain barrier (BBB) disruption or changes in permeability. Among both the 0-3 hour and 3-6 hour groups the primary measure of safety will be to not tolerate greater than a 10% rate of symptomatic intracerebral hemorrhage (sICH) within 24 hours.
* The primary hypothesis is that replacing conventional TCD ultrasound hand-held TCD technology with a Hands-Free system will be safe in healthy volunteers as well as acute ischemic stroke patients.
If the device is found to be safe in either the 0-3 hour or 3-6 hour groups,
- the secondary aims for this study will explore the rates of arterial recanalization in the 0-3 hour and/or 3-6 hour groups, favorable outcomes, and clinical recovery. The secondary aims will assess the hypothesis is that Hands-Free TCD will display similar recanalization and early clinical recovery rates compared to available historical diagnostic TCD ultrasound controls exposed to conventional FDA-approved TCD technology.
Data generated during this phase I/II trial will evaluate the safety of replacing an operator-dependent TCD device with an operator-independent unit. In turn, this will allow extensive availability of therapeutic ultrasound and improve enrollment into ultrasound-enhanced thrombolysis stroke trials.

Conditions

Interventions

  • Hands Free Transcranial (HF-TCD) Ultrasound Device Procedure/Surgery
    Intervention Desc: A hands-free transcranial (HF-TCD) ultrasound device which delivers ultrasound to the principal regions in which vessel occlusions in the brain are known to occur. The device is designed to simplify the process of delivering safe levels of of ultrasound through the skull for the treatment of ischemic stroke. The device incorporates features that enable fast, easy to use access in the emergency room environment. The initial point of medical care contact for most stroke patients.
  • 2-MHz transcranial Doppler ultrasound Device
    Other Names: transcranial Doppler Ultrasound; ultrasound
    Intervention Desc: 2-hours of hands-free ultrasound will be insonated continuously. A brain MRI with gadolinium will be performed before and after the ultrasound.
    ARM 1: Kind: Experimental
    Label: Phase I: Healthy Volunteers
    Description: Subjects without history of central nervous system disease.
  • 2-MHz transcranial Doppler ultrasound insonation Device
    Other Names: transcranial Doppler ultrasound; ultrasound; sonothrombolysis
    Intervention Desc: 2-hours of hands-free ultrasound delivered to in the intracranial vessels.
    ARM 1: Kind: Experimental
    Label: Phase II: 0-3 hour Patients
    Description: Ischemic stroke patients who present between 0-3 hours.
  • 2-MHz ultrasound insonation +/- microbubbles Device
    Other Names: transcranial Doppler ultrasound; ultrasound; sonothrombolysis
    Intervention Desc: 2-hours of hands-free ultrasound delivered to in the intracranial vessels. Intravenous microbubbles.
    ARM 1: Kind: Experimental
    Label: Phase II: 3-6 hour patients
    Description: Ischemic Stroke patients who present between 3 and 6 hours.

Trial Design

  • Allocation: Non-Randomized
  • Masking: Open Label
  • Purpose: Treatment
  • Endpoint: Safety Study
  • Intervention: Single Group Assignment

Patient Involvement

The primary specific aim for this pilot phase I/II study is to assess the safety of a novel, external Hands-Free TCD ultrasound system. Safety of the new Hands-Free TCD system will first be assessed in healthy volunteers. Safety in these participants will be determined by detailed neurological and dermatological exams and MRI imaging of the brain. Next, safety of the device will be evaluated in two distinct sets of acute ischemic stroke patients: 0-3 hour patients treated with standard IV rt-PA and 3-6 hour non-lytic, image-selected patients treated with sonolysis (with or without intravenous microbubbles). Among the healthy volunteers the primary measures of safety will be to have no detectable changes in a detailed neurological exam nor any BBB disruption or changes in permeability. Among both the 0-3 hour and 3-6 hour groups the primary measure of safety will be to not tolerate greater than a 10% rate of sICH within 24 hours.

Outcomes

Type Measure Time Frame Safety Issue
Primary Safety: blood-brain-barrier disruption or deterioration in neurological examination. Phase I : Determine if the Hands-Free TCD system results in deterioration in the neurological examination or result in any BBB-disruption or deterioration in permeability as measured by MRI of the brain. Safety as measured by incidence of symptomatic intracerebral hemorrhage Phase II: Determine if the Hands-Free TCD will not result in higher than 10% rate of symptomatic intracerebral ICH within 24 hours (defined as clinical worsening > 4 NIHSS points and presence of hemorrhage on CT scan that in the opinion of the treating physician is causatively related to ICH on CT) in 0-3 hours acute stroke patients treated with IV-rt-PA.
Secondary Phase 1 (healthy volunteers): Assess feasibility and activity of the HF TCD. Feasibility and activity will be assessed by whether the HF TCD can reach standard TCD levels. Subject complaints regarding discomfort of the device will be assessed. A detailed physical examination of skin integrity post-insonation will determine any local dermatological adverse events. Phase II study: Arterial Recanalization Ischemic stroke patients: 2-hour rates of arterial complete and partial recanalization as measured using standard Transcranial Doppler Ultrasound systems. Phase II study: Clinical recovery Ischemic stroke patients: rates of clinical recovery at 2 and 24 hours post treatment, dramatic early clinical recovery (NIHSS ? 3) at 2 hours, early clinical recovery (reduction of NIHSS ? 10 points), neurologic improvement (reduction of ? 4 points or total NIHSS score ? 3), and rates of complete recovery. Phase II study: Neurological worsening Ischemic stroke patients: rates of neurological worsening. Phase II study: Clinical outcome at 3 months Ischemic stroke patients: rates of good recovery (mrs 0 or 1) and NIH Stroke scale scores at 3 months
Primary Safety: blood-brain-barrier disruption or deterioration in neurological examination. up to 2-years Yes
Primary Safety as measured by incidence of symptomatic intracerebral hemorrhage up to 3 years Yes
Secondary Phase 1 (healthy volunteers): Assess feasibility and activity of the HF TCD. up to 2 years Yes
Secondary Phase II study: Arterial Recanalization up to 3 years No
Secondary Phase II study: Clinical recovery up to 3 years No
Secondary Phase II study: Neurological worsening up to 3 years Yes
Secondary Phase II study: Clinical outcome at 3 months up to 3 years No
Primary Number of Participants in Phase I Group With Blood-brain-barrier Disruption (BBB) as Measured by MRI of the Brain 2-3 hours after treatment Yes
Primary Safety in Phase II Group as Measured by Incidence of Symptomatic Intracerebral Hemorrhage within 24 hours Yes
Primary Number of Participants in Phase I Group With Neurological Deterioration as Measured by Neurological Examination 2-3 hours after treatment Yes
Secondary Number of Participants in Phase I Group With Adverse Events During and After Study Treatment With HF TCD 2-3 hours after treatment Yes
Secondary Percentage of Participants in the Phase II Group That Show Arterial Recanalization as Measured Using Standard Transcranial Doppler Ultrasound Systems 2-3 hours after treatment No
Secondary Percentage of Participants in Phase II Group With Neurological Worsening as Determined by the NIH Stroke Scale within 90 days of enrollment Yes
Secondary Percentage of Participants in Phase II Group With Excellent Outcome as Measured by Modified Rankin Scale (mRS) at 3-months from enrollment No

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