Safety Study of Nicardipine to Treat Cerebral Vasospasm

Subarachnoid hemorrhage accounts for approximately 5% of all strokes and affects 30,000
Americans per year. Poor outcome from aneurysmal subarachnoid hemorrhage (SAH) occurs in 50
to 75% of patients, and this is attributed to secondary ischemia in approximately 30% of
patients. This delayed cerebral ischemia has been attributed to the anatomic narrowing of
arteries in the cerebral vasculature which occurs following SAH.

Because of this relationship between cerebral vasospasm, cerebral ischemia, and poor
outcome, there has been significant effort to establish treatments that decrease the
incidence of vasospasm after SAH. Currently, medications and hemodynamic maneuvers are used
as standard of care for the treatment of vasospasm and to improve outcome after SAH.

The calcium channel blocker, nimodipine, is one of the few treatments for vasospasm that has
been shown to be of proven benefit. Nicardipine is another calcium channel blocker that has
been evaluated in several studies via an intravenous administration route. These studies
did show significant improvements in symptomatic and angiographic vasospasm, although a
benefit in outcome was not seen. However, the intravenous administration of nicardipine was
associated with significant systemic side effects that may have affected outcome including
hypotension, pulmonary edema, and azotemia.

The administration of nicardipine via an intrathecal route avoids the systemic complications
associated with intravenous dosing since the direct cerebrospinal fluid dosing is much
lower. The result is that the systemic concentration will remain low avoiding systemic side
effects, and central nervous system concentration will remain high. We propose that this
difference may improve outcomes while minimizing complication related effects on patient
outcomes.

Inclusion Criteria:

- Male or female 18 years of age and older

- Subarachnoid hemorrhage documented on head CT

- Fisher Grade 3 or 4

- Hunt Hess Grade 2 or greater

- Cerebral aneurysm as definitive source of subarachnoid hemorrhage

- Cerebral aneurysm must be treated via open or endovascular techniques

- Presence of external ventricular drain

- Written informed consent obtained from subject or subject's legally authorized
representative

Exclusion Criteria:

- Absence or inability to have an external ventricular drain (coagulopathy)

- Non-aneurysmal subarachnoid hemorrhage (perimesencephalic)

- Untreated cerebral aneurysm

- Inability to be randomized prior to post-hemorrhage day 4

- Elevated intra-cranial pressures that would preclude external ventricular drain
clamping for 30-60 minutes

- Inability to administer study medication (severe intra-ventricular hemorrhage,
occluded external ventricular drain)

- Inability to obtain angiography (coagulopathy, renal failure)

- Pregnant

- Presence of a condition or abnormality that in the opinion of the Investigator would
compromise the safety of the patient or the quality of the data