CLOTBUST Hands-Free

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.