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

Phase 1

Completed

Conditions: Stroke

Interventions: Device: 2-MHz transcranial Doppler ultrasound
Device: 2-MHz transcranial Doppler ultrasound insonation

Registration Number: NCT01240356

Lead Sponsor: The University of Texas Health Science Center, Houston

Brief Summary: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 35

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase I: Healthy Volunteers	2-MHz transcranial Doppler ultrasound	Subjects without history of Central Nervous System Disease will receive 2-hours of hands-free 2-megahertz (MHz) transcranial Doppler ultrasound insonation continuously. A brain MRI with gadolinium will be performed before and after the ultrasound.
Phase II: 0-3 hour Patients	2-MHz transcranial Doppler ultrasound insonation	Ischemic stroke patients who present between 0-3 hours will receive 2-hours of hands-free 2-MHz transcranial Doppler ultrasound Continuously to the intracranial vessels.

Primary Outcome Measures

Name	Time	Method
Safety in Phase II Group as Measured by Incidence of Symptomatic Intracerebral Hemorrhage	within 24 hours	Phase II: Determine if the Hands-Free TCD will not result in higher than 10% rate of symptomatic intracerebral hemorrhage (ICH) within 24 hours (defined as clinical worsening \> 4 NIH Stroke Scale (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 intravenous tissue-type plasminogen activator (IV-t-PA).
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	Phase I : Imaging of the brain via MRI scans was performed to determine if the Hands-Free transcranial Doppler (TCD) system results in any BBB-disruption or deterioration in permeability.
Number of Participants in Phase I Group With Neurological Deterioration as Measured by Neurological Examination	2-3 hours after treatment	The neurological examinations comprised assessments of mental status and orientation, cranial nerve examination, muscle strength and tone, deep tendon reflexes, sensory testing, coordination, and gait.

Secondary Outcome Measures

Name	Time	Method
Number of Participants in Phase I Group With Adverse Events During and After Study Treatment With HF TCD	2-3 hours after treatment	Phase I - A group of healthy volunteers will be assessed to determine the feasibility and activity of hands-free (HF) transcranial Doppler (TCD). Adverse events include subject complaints regarding discomfort of the device and dermatological adverse events as evidenced by a detailed physical examination of skin integrity post-insonation.
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	Ischemic stroke patients: 2-hour rates of arterial complete and partial recanalization as measured using standard Transcranial Doppler Ultrasound systems.
Percentage of Participants in Phase II Group With Neurological Worsening as Determined by the NIH Stroke Scale	within 90 days of enrollment	The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. Each item on the NIHSS scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.
Percentage of Participants in Phase II Group With Excellent Outcome as Measured by Modified Rankin Scale (mRS)	at 3-months from enrollment	A modified Rankin Scale (mRS) score of 0 or 1 indicates an excellent outcome. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The mRS scale ranks patients from 0 to 6 (0 is the best score, 6 is the worst score).