CLOTBUST Hands-Free: A Phase I/II Pilot Safety 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 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.

Inclusion criteria

Phase I Safety (healthy volunteers):

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

Phase II (0-3 hours ischemic stroke patients):

• Disabling focal neurological deficit (NIHSS > 4 points);
• No evidence of hemorrhage on non-contrast head CT scan;
• 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;
• Diagnostic TCD completed and HF-TCD placed before rt-PA bolus.
• 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.
• Age ≥ 18 years old.
• Signed informed consent.

Phase II (3-6 hours ischemic stroke patients):

• Measurable focal neurological deficit (NIHSS > 4 points);
• No evidence of hemorrhage on non-contrast head CT scan;
• 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.
• Presence of neuroimaging defined mismatch (CT or MRI prior to enrollment)

• CT-perfusion

• ≥ 20% difference between affected territories on Time to Peak (TTP) and Cerebral Blood Volume (CBV) maps.
• MRI Diffusion-Perfusion mismatch

• ≥ 20% difference between diffusion-weighted imaging (DWI) lesion and territory of perfusion delay perfusion weighted imaging (PWI).
• Age ≥ 18 years old.
• Signed informed consent.

Exclusion criteria

Phase I Safety (healthy volunteers):

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

Phase II (0-3 hours ischemic stroke patients):

• Absent temporal windows in patients with anterior circulation ischemia;
• Intra-arterial thrombolysis;
• Patient refusal to give informed consent to participate in the CLOTBUST-HF trial;
• Contraindications for intravenous rt-PA (NINDS rt-PA Stroke Study Protocol)2.
• Phase II (3-6 hours ischemic stroke patients):
• Absent temporal windows in patients with anterior circulation ischemia;
• Intra-arterial thrombolysis;
• Patient refusal to give informed consent to participate in the CLOTBUST-HF trial;
• History of allergic response to Definity® microspheres or microbubbles currently being tested (MRX-801);
• Baseline imaging consistent with a malignant ischemic pattern (low CBV values or DWI territory >100cc of tissue);
• Baseline MRI imaging demonstrating delayed perfusion of > 8 seconds in >100cc of brain parenchyma26;
• Patients receiving other investigational drugs, procedures, or therapies within 30 days prior to study treatment;
• 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;
• Known severe chronic obstructive pulmonary disease (COPD) (baseline oxygen saturation < 80% on room air);
• Known right-to-left cardiac shunt.