Antihypertensive Treatment of Acute Cerebral Hemorrhage-II
Condition: Intracerebral Hemorrhage
MeSH terms: Cerebral Hemorrhage; Hemorrhage
Intervention: Intravenous nicardipine hydrochloride
Intervention description: IV nicardipine is initiated at a rate of 5 mg/hr, is continued, and is increased by 2.5 mg/hr increments every 15 min until the target SBP or maximum dose of 15 mg/hr is reached. If SBP is above the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent may be used (Labetalol 5-20 mg IV bolus every 15 min; diltiazem/urapidil in countries without labetalol) for another hour. Nicardipine infusion is decreased incrementally or is stopped if SBP falls below the desired treatment range.
Fluid bolus for SBP still falling below 110 mmHG (millimeters of mercury) with nicardipine off is given to prevent organ hypoperfusion. Vasopressor agents are not used unless symptoms related to or possibly exacerbated by hypoperfusion are present.
Intervention MeSH terms: Nicardipine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Eligible patients are randomized 1:1 via computer-generated treatment assignment within 4.5 hours of neurological symptom onset to either standard or intensive SBP management using intravenous nicardipine hydrochloride as the primary BP control agent through 24 hours from randomization. Enrolled patients from both treatment arms are otherwise treated similarly after 24 hours, according to their medical needs. Standards of care management for spontaneous intracerebral hemorrhage published in the 2010 American Heart Association guidelines are incorporated in to the study protocol. All enrolled patients are followed through 90 days (± 14 days per protocol window; up to ± 30 days data is used) unless death or withdrawal occurs sooner. Primary analysis based on intent-to-treat (ITT) principles.
Masking: Double (Investigator, Outcomes Assessor)
Masking description: The trial intervention is conducted open-label to avoid concealing clinically necessary patient blood pressure and intravenous drug administration information. Clinical data including SBP values are primarily taken from entries recorded in to the patient's official medical record by hospital staff and are independently monitor-verified. Assessors for the primary outcome (mRS) at 90 days are are unaware of the treatment assignment or in-hospital clinical course of the subjects assessed. De-identified imaging studies are coded independently of subject number so the central imaging reader is unaware of the treatment assignment, clinical findings, or time points of image acquisition for data recorded from imaging. The study (lead) principal investigator and leadership committee members are unable to associate the treatment assignment of subjects to their outcomes or adverse events for purposes of trial decision-making. Adverse events are adjudicated by an independent oversight committee.
Enrollment: 1000.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute hypertensive response; intracerebral hemorrhage; blood pressure; outcome; nicardipine

Summary:

      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.
    

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.