Antihypertensive Treatment of Acute Cerebral Hemorrhage-II
Antihypertensive Treatment of Acute Cerebral Hemorrhage-II
The specific aims of this study are to:

 1. Definitively determine the therapeutic benefit of the intensive treatment relative to
 the standard treatment in the proportion of patients with death and disability (mRS 4-6)
 at 3 months among subjects with ICH who are treated within 4.5 hours of symptom onset.

 2. Evaluate the therapeutic benefit of the intensive treatment relative to the standard
 treatment in the subjects' quality of life as measured by EuroQol at 3 months.

 3. Evaluate the therapeutic benefit of the intensive treatment relative to the standard
 treatment in the proportion of hematoma expansion (defined as increase from baseline
 hematoma volume of at least 33%) and in the change from baseline peri-hematoma volume at
 24 hours on the serial computed tomographic (CT) scans.

 4. Assess the safety of the intensive treatment relative to the standard treatment in the
 proportion of subjects with treatment-related serious adverse events (SAEs) within 72
 hours.
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 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.

 -  Notes: The unit "mmHg" stands for "millimeters of mercury", a standard way of
 measuring blood pressure. Patients with SBP < 180 mmHg 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 50,000 per microliter (µL or mm3)

 -  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

 -  Use of dabigatran was clarified through investigator presentations, educational
 materials, and clinical tools to include newer similar class medications (such as
 rivaroxaban, apixaban, and edoxaban) that were being developed and in various
 stages of approval across enrolling countries through the course of this trial,
 in the event that patients using these medications may have been encountered
 during screening.