The Spot Sign for Predicting and Treating ICH Growth Study

Intracerebral hemorrhage (ICH)—breakage of a blood vessel with bleeding in the brain—is a
devastating form of stroke with a 40-50 percent fatality rate and no proven treatment.
Because the majority of deaths from ICH occur within several days of the stroke,
interventions for improving outcomes must occur early in the treatment course. Among the
potentially modifiable determinants of ICH outcome, hematoma growth is a particularly
attractive target for intervention and a major focus of this trial.

The purpose of this study is to determine if an imaging test called computed tomography
angiography (CTA) can predict which individuals with ICH will experience significant growth
in the size of the hemorrhage. Growth of the hemorrhage can cause additional injury and may
worsen the outcome. For individuals who are at high risk for hemorrhage growth based on CTA
results (i.e., a positive CTA "spot sign," evidence of contrast leakage within the
hemorrhage), the study will compare the effects of a drug called recombinant activated factor
VII (NovoSeven®) or rFVIIa with a placebo to determine which is better for reducing ICH
growth.

The primary goals of this trial are (1) to determine the sensitivity and specificity of the
CTA spot sign for predicting hematoma growth; (2) to determine the feasibility of using CTA
to identify individuals with ICH who are at high risk of hematoma growth and to select study
participants for randomization to treatment with rFVIIa or placebo; and (3) to determine the
rate of hematoma growth among spot-positive individuals at 24 hours—comparing individuals
treated with rFVIIa to those treated with placebo.

Approximately 184 persons with ICH will be enrolled in one of two study groups at 12 clinical
sites across the United States and Canada. Participants with ICH who are determined by CTA to
be at high risk for hemorrhage growth (CTA "spot sign" positive) will be randomized to
receive either the active study medication, rFVIIa, at 80 mcg/kg, or to receive a placebo (an
inactive substance). Participants with ICH who are determined by CTA not to be at high risk
for hemorrhage growth (determined to be CTA "spot sign" negative) will be enrolled into a
prospective observational group.

Duration of the study for participants is approximately 3 months.

Inclusion Criteria:

- Acute, spontaneous ICH (including bleeding in cerebellum) diagnosed by non-enhanced CT
scan within five hours of symptom onset. (Time of onset is defined as the last time
the patient was witnessed to be at baseline (i.e., subjects who have stroke symptoms
upon awakening will be considered to have their onset at beginning of sleep)

- Age >/= 18 years through 80 years (candidates must have had their 18th birthday, but
not had their 81st birthday)

- For spot positive patients, dosing of study drug within 90 minutes of enrolling CT
scan

Exclusion Criteria:

- Time of symptom onset of ICH is unknown or more than five hours prior to baseline CT
scan,

- ICH secondary to known or suspected trauma, aneurysm, vascular malformation,
hemorrhagic conversion of ischemic stroke, venous sinus thrombosis, thrombolytic
treatment of any condition (e.g., myocardial infarction, cerebral infarction, etc.),
central nervous system (CNS) tumor or CNS infection

- Brainstem location of hemorrhage (patients with cerebellar hemorrhage may be enrolled)

- Serum creatinine > 1.4 mg/dl (123 μmol/L). Sites that currently perform CTA as
standard of care for ICH will follow their standard procedures regarding renal
insufficiency.

- Known allergy to iodinated contrast media

- Intravenous or intra-arterial administration of iodinated contrast media within the
previous 24 hours of baseline CT scan

- Known hereditary (e.g., hemophilia) or acquired hemorrhagic diathesis, coagulation
factor deficiency, or anticoagulant therapy with international normalized ration (INR)
> 1.2

- Known or suspected thrombocytopenia (unless current platelet count documented above
50,000 / μl)

- Unfractionated heparin use with abnormal partial thromboplastin time (PTT)

- Low-molecular weight heparin use within the previous 24 hours

- GPIIb/IIIa antagonist use in the previous two weeks

- Direct thrombin inhibitor or factor Xa inhibitor within the previous 48 hours

- Glasgow Coma Scale score < 8 at time of proposed enrollment

- Pre-admission modified Rankin Scale score > 2

- Baseline ICH volume of < 0.5 cc (Hematoma volume will be estimated by local
investigators from the baseline CT using the "ABC / 2 method".)

- Baseline ICH volume of > 90 cc

- Planned surgical evacuation of ICH within 24 hours of symptom onset (placement of
intraventricular catheter is not a contraindication to study enrollment.)

- Evidence of acute or subacute ischemic stroke on baseline qualifying CT scan

- Clinical history of thromboembolism or ischemic vascular disease, including myocardial
infarction, coronary artery bypass surgery, cardiac angina, transient ischemic attack,
ischemic stroke, peripheral artery disease (vascular claudication), cerebral bypass
surgery, carotid endarterectomy, deep venous thrombosis, pulmonary embolism, or
coronary or cerebrovascular angioplasty or stenting. (Clinically silent evidence of
old ischemia on EKG (Q waves) or CT scan (silent old infarct) will not be considered
reasons for exclusion.)

- Baseline electrocardiogram shows evidence of acute cardiac ischemia (ST elevation in
two contiguous leads, new left bundle branch block (LBBB), or ST depression)

- Clinical history suggestive of acute cardiac ischemia (e.g., chest pain)

- Abnormal baseline troponin

- Females of childbearing potential who are known to be pregnant and/or lactating or who
have positive pregnancy tests on admission

- Advanced or terminal illness or any other condition the investigator feels would pose
a significant hazard to the patient if rFVIIa were administered

- Recent (within 30 days) participation in any investigational drug or device trial or
earlier participation in any investigational drug or device trial for which the
duration of effect is expected to persist until the time of STOP-IT enrollment

- Planned withdrawal of care or comfort care measures

- Patient known or suspected of not being able to comply with trial protocol (e.g., due
to alcoholism, drug dependency or psychological disorder)

- Informed consent cannot be obtained from the patient or legally authorized
representative