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.

Eligibility Criteria:
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.