Antihypertensive Treatment of Acute Cerebral Hemorrhage-II

The report from a National Institute of Neurological Disorders and Stroke Workshop on
priorities for clinical research in intracerebral hemorrhage (ICH) in December 2003
recommended clinical trials for evaluation of blood pressure (BP) management in acute ICH as
a leading priority. The Special Writing Group of the Stroke Council of the American Heart
Association in 1999 and 2007 emphasized the need for clinical trials to ensure
evidence-based treatment of acute hypertension in ICH. Consequently, we propose to conduct a
five-year international, multicenter, open-labeled, randomized, controlled, Phase III trial
to determine the efficacy of early, intensive antihypertensive treatment using intravenous
nicardipine for acute hypertension in subjects with co-morbid hypertension and spontaneous
supratentorial ICH. The primary hypothesis of this large, streamlined, focused trial is that
the group treated with intensive BP reduction (systolic BP [SBP] of 140 mmHg or less -
hereafter referred to as the intensive treatment) using intravenous nicardipine infusion for
24 hours reduces the proportion of death and disability at 3 months by 10% or greater
compared with the group treated with the standard BP reduction (SBP of 180 mmHg or less -
hereafter referred to as the standard treatment) among patients with ICH treated within 4.5
hours of symptom onset. The underlying mechanism for this expected beneficial effect of
intensive treatment is mediated through reduction of the rate and magnitude of hematoma
expansion observed in approximately 38% of patients with acute ICH. The trial will recruit a
maximum of 1,280 subjects with ICH who meet the eligibility criteria. The primary outcome is
the proportion of death and disability at 3 months defined by modified Rankin scale (mRS)
score of 4 to 6. The proposed clinical trial is the natural extension of numerous case
series, a subsequent pilot trial funded by the National Institutes of Health National
Institute of Health (NIH), and a preliminary randomized controlled trial in this patient
group funded by the Australian National Health and Medical Research Council, that have
recently confirmed the safety and tolerability of both the regimen and goals of the
antihypertensive treatment in acutely hypertensive patients with ICH proposed in the present
trial. The proposed trial will have important public health implications by providing
necessary information regarding the efficacy and safety of antihypertensive treatment of
acute hypertension observed in up to 75% of the subjects with ICH. BP treatment represents a
strategy that can be made widely available without the need of specialized equipment and
personnel and therefore can make a major impact upon outcome in patients with ICH.
Substantial reduction in morbidity and mortality appears possible if the estimates of
treatment effect sizes from our current pilot trials are accurate.

Inclusion Criteria:

- Age 18 years or older

- IV nicardipine can be initiated within 4.5 hours of symptom onset.

- Clinical signs consistent with the diagnosis of stroke, including impairment of
language, motor function, cognition, and/or gaze, vision, or neglect.

- Total Glasgow Coma Scale (GCS) score (aggregate of verbal, eye, and motor response
scores) of 5 or greater at time of emergency department (ED) arrival.

- International normalized ratio (INR) value < 1.5

- CT scan demonstrates intraparenchymal hematoma with manual hematoma volume
measurement <60 cc.

- For subjects randomized prior to IV antihypertensive administration: SBP greater than
180 mmHg* prior to IV antihypertensive treatment (this includes pre-hospital
treatment) AND WITHOUT spontaneous SBP reduction to below 180 mmHg at the time of
randomization OR

- For subjects randomized after IV antihypertensive administration: SBP greater than
180 mmHg* prior to IV antihypertensive treatment (this includes pre-hospital
treatment) AND WITHOUT SBP reduction to below 140 mmHg at the time of randomization.

- Informed consent obtained by subject, legally authorized representative, or next of
kin.

- Note: Patients with SBP < 180mmHg should be monitored for 4.5 hours from symptom
onset as their SBP may rise to eligible levels before the eligibility window
closes.

Exclusion Criteria:

- ICH is due to previously known neoplasms, arteriovenous malformation (AVM), or
aneurysms.

- Intracerebral hematoma considered to be related to trauma.

- ICH located in infratentorial regions such as pons or cerebellum.

- Intraventricular hemorrhage (IVH) associated with intraparenchymal hemorrhage and
blood completely fills one lateral ventricle or more than half of both ventricles.

- Patient to receive immediate surgical evacuation.

- Current pregnancy, or parturition within previous 30 days, or active lactation.

- Use of dabigatran within the last 48 hours.

- A platelet count less than 50,000mm3

- Known sensitivity to nicardipine.

- Pre-morbid disability requiring assistance in ambulation or activities of daily
living.

- Subject's living will precludes aggressive ICU management.

- Subject is currently participating in another interventional clinical trial