Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III

Primary Objectives:

Efficacy: Demonstrate that minimally invasive surgery (MIS) plus recombinant tissue
plasminogen activator (rt-PA) for three days improves functional outcome by a 12% increase in
the modified Rankin Scale (mRS) score 0-3 compared to medically treated subjects assessed at
365 days.

Secondary Objective:

Demonstrate that the end of treatment volume and percent of ICH reduction from MIS+rt-PA is
related to improved functional outcome, as compared to medically treated subjects.

Safety:

Demonstrate that early use of MIS+rt-PA for three days is safe for the treatment of ICH
relative to rates of mortality, rebleeding, and infection in the medically treated subject at
30 days.

Inclusion Criteria:

- Spontaneous supratentorial ICH ≥ 30 mL diagnosed using radiographic imaging
(computerized tomography (CT), computerized tomography angiography (CTA), etc.), with
a Glasgow Coma Scale (GCS) ≤ 14 or a NIHSS ≥ 6.

- Stability CT scan done at least 6 hours after diagnostic CT showing clot stability
(growth < 5 mL as measured by ABC/2 method).

- Symptoms less than 24 hours prior to diagnostic CT (dCT) scan (an unknown time of
onset is exclusionary).

- Ability to randomize between 12 and 72 hours after dCT.

- Systolic Blood Pressure (SBP) < 180 mmHg sustained for six hours recorded closest to
the time of randomization.

- Historical Rankin score of 0 or 1.

- Age ≥ 18 and older.

Exclusion Criteria:

- Infratentorial hemorrhage.

- Intraventricular hemorrhage (IVH) requiring treatment for IVH-related (casting) mass
effect or shift due to trapped ventricle. External ventricular drain (EVD) to treat
intracranial pressure (ICP) is allowed.

- Thalamic bleeds with apparent midbrain extension with third nerve palsy or dilated and
non-reactive pupils. Other (supranuclear) gaze abnormalities are not exclusions. Note:
Patients with a posterior fossa ICH or cerebellar hematomas are ineligible.

- Irreversible impaired brain stem function (bilateral fixed, dilated pupils and
extensor motor posturing), GCS ≤ 4.

- Ruptured aneurysm, arteriovenous malformation (AVM), vascular anomaly, Moyamoya
disease, hemorrhagic conversion of an ischemic infarct, recurrence of a recent (< 1
year) hemorrhage diagnosed with radiographic imaging.

- Patients with unstable mass or evolving intracranial compartment syndrome.

- Platelet count < 100,000; international normalized ratio (INR) > 1.4.

- Any irreversible coagulopathy or known clotting disorder.

- Inability to sustain INR ≤ 1.4 using short- and long-active procoagulants (such as but
not limited to NovoSeven, Fresh Frozen Plasma (FFP), and/or vitamin K).

- Subjects requiring long-term anti-coagulation are excluded. Reversal of
anti-coagulation is permitted for medically stable patients who can realistically
tolerate the short term risk of reversal. Patient must not require Coumadin
(anticoagulation) during the first 30 days, and normalized coagulation parameters must
be demonstrated, monitored closely and maintained during the period of brain
instrumentation.

- Use of Dabigatran, Apixaban, and/or Rivaroxaban (or a similar medication from the
similar medication class) prior to symptom onset.

- Internal bleeding, involving retroperitoneal sites, or the gastrointestinal,
genitourinary, or respiratory tracts.

- Superficial or surface bleeding, observed mainly at vascular puncture and access sites
(e.g., venous cutdowns, arterial punctures, etc.) or site of recent surgical
intervention.

- Positive urine or serum pregnancy test in pre-menopausal female subjects without a
documented history of surgical sterilization.

- Allergy/sensitivity to rt-PA.

- Prior enrollment in the study.

- Participation in a concurrent interventional medical investigation or clinical trial.
Patients in observational, natural history, and/or epidemiological studies not
involving an intervention are eligible.

- Not expected to survive to the day 365 visit due to co-morbidities and/or are do not
resuscitate (DNR)/ do not intubate (DNI) status prior to randomization.

- Any concurrent serious illness that would interfere with the safety assessments
including hepatic, renal, gastroenterologic, respiratory, cardiovascular,
endocrinologic, immunologic, and hematologic disease.

- Patients with a mechanical heart valve. Presence of bio-prosthetic valve(s) is
permitted.

- Known risk for embolization, including history of left heart thrombus, mitral stenosis
with atrial fibrillation, acute pericarditis, or subacute bacterial endocarditis.

- Any other condition that the investigator believes would pose a significant hazard to
the subject if the investigational therapy were initiated.

- Active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with adherence to study requirements.

- In the investigator's opinion, the patient is unstable and would benefit from a
specific intervention rather than supportive care plus or minus MIS+rt-PA removal of
the ICH.

- Inability or unwillingness of subject or legal guardian/representative to give written
informed consent.