CLOTBUST Hands-Free (CLOTBUST-HF)

• Safety: blood-brain-barrier disruption or deterioration in neurological examination. [ Time Frame: up to 2-years ] [ Designated as safety issue: Yes ]
  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 [ Time Frame: up to 3 years ] [ Designated as safety issue: Yes ]
  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.

• Phase 1 (healthy volunteers): Assess feasibility and activity of the HF TCD. [ Time Frame: up to 2 years ] [ Designated as safety issue: Yes ]
  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 [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  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 [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

  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).
  • Rates of complete recovery.
• Phase II study: Neurological worsening [ Time Frame: up to 3 years ] [ Designated as safety issue: Yes ]
  Ischemic stroke patients: rates of neurological worsening.
• Phase II study: Clinical outcome at 3 months [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  Ischemic stroke patients: rates of good recovery (mrs 0 or 1) and NIH Stroke scale scores at 3 months.

The purpose of CLOTBUST-HF is to determine the safety of a novel, external Hands-Free transcranial Doppler 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.

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 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.

* 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.

• Healthy Volunteers
• Ischemic Stroke

• Device: 2-MHz transcranial Doppler ultrasound
  2-hours of hands-free ultrasound will be insonated continuously. A brain MRI with gadolinium will be performed before and after the ultrasound.
  Other Names:

  • transcranial Doppler Ultrasound
  • ultrasound
• Device: 2-MHz transcranial Doppler ultrasound insonation
  2-hours of hands-free ultrasound delivered to in the intracranial vessels.
  Other Names:

  • transcranial Doppler ultrasound
  • ultrasound
  • sonothrombolysis
• Device: 2-MHz ultrasound insonation +/- microbubbles
  2-hours of hands-free ultrasound delivered to in the intracranial vessels. Intravenous microbubbles.
  Other Names:

  • transcranial Doppler ultrasound
  • ultrasound
  • sonothrombolysis

• Experimental: Phase I: Healthy Volunteers
  Subjects without history of central nervous system disease.
  Intervention: Device: 2-MHz transcranial Doppler ultrasound
• Experimental: Phase II: 0-3 hour Patients
  Ischemic stroke patients who present between 0-3 hours.
  Intervention: Device: 2-MHz transcranial Doppler ultrasound insonation
• Experimental: Phase II: 3-6 hour patients
  Ischemic Stroke patients who present between 3 and 6 hours.
  Intervention: Device: 2-MHz ultrasound insonation +/- microbubbles

INCLUSION CRITERIA

Phase I Safety (healthy volunteers)

1. Presence of temporal windows as measured first by an FDA-approved diagnostic TCD device.
2. Age ≥ 18 years old.
3. Signed informed consent.

Phase II (0-3 hours ischemic stroke patients)

1. Disabling focal neurological deficit (NIHSS > 4 points);
2. No evidence of hemorrhage on non-contrast head CT scan;
3. Intravenous rt-PA (0.9 mg/kg, 10% bolus 90% infusion over 1 hour, maximum dose 90 mg) infusion initiated within 3 hours of symptom onset;
4. Diagnostic TCD completed and HF-TCD placed before rt-PA bolus.
5. Diagnostic TCD confirms intracranial arterial occlusion of the middle cerebral artery (MCA), anterior cerebral artery (ACA), internal carotid artery (ICA), posterior cerebral artery (PCA) or distal basilar artery.
6. Age ≥ 18 years old.
7. Signed informed consent.

Phase II (3-6 hours ischemic stroke patients)

1. Measurable focal neurological deficit (NIHSS > 4 points);
2. No evidence of hemorrhage on non-contrast head CT scan;
3. Diagnostic TCD confirms intracranial arterial occlusion of the middle cerebral artery (MCA), anterior cerebral artery (ACA), internal carotid artery (ICA), posterior cerebral artery (PCA) or distal basilar artery.

4. Presence of neuroimaging defined mismatch (CT or MRI prior to enrollment)

   a. CT-perfusion i. ≥ 20% difference between affected territories on Time to Peak (TTP) and Cerebral Blood Volume (CBV) maps.

   b. MRI Diffusion-Perfusion mismatch i. ≥ 20% difference between DWI lesion and territory of perfusion delay (PWI).

5. Age ≥ 18 years old.
6. Signed informed consent.

EXCLUSION CRITERIA

Phase I Safety (healthy volunteers)

1. History of any neurological disease affecting the central nervous system;
2. Lack of temporal windows.
3. History of renal disease or glomerular filtration rate (GFR) < 60.
4. Contraindication to MRI (e.g., pacemaker, spinal cord stimulator, severe claustrophobia)

Phase II (0-3 hours ischemic stroke patients)

1. Absent temporal windows in patients with anterior circulation ischemia;
2. Intra-arterial thrombolysis;
3. Patient refusal to give informed consent to participate in the CLOTBUST-HF trial;
4. Contraindications for intravenous rt-PA (NINDS rt-PA Stroke Study Protocol)2.

Phase II (3-6 hours ischemic stroke patients)

1. Absent temporal windows in patients with anterior circulation ischemia;
2. Intra-arterial thrombolysis;
3. Patient refusal to give informed consent to participate in the CLOTBUST-HF trial;
4. History of allergic response to Definity® microspheres or microbubbles currently being tested (MRX-801);
5. Baseline imaging consistent with a malignant ischemic pattern (low CBV values or DWI territory >100cc of tissue);
6. Baseline MRI imaging demonstrating delayed perfusion of > 8 seconds in >100cc of brain parenchyma26;
7. Patients receiving other investigational drugs, procedures, or therapies within 30 days prior to study treatment;
8. Significant concurrent medical/neurological conditions or deviation from normal laboratory test values at baseline that, in the opinion of the investigator, pose significant risk to the patient and warrant exclusion from the study;
9. Known severe COPD (baseline oxygen saturation < 80% on room air);
10. Known right-to-left cardiac shunt.