Antihypertensive Treatment of Acute Cerebral Hemorrhage-II

Phase 3

Terminated

Conditions: Intracerebral Hemorrhage

Interventions: Drug: Intravenous nicardipine hydrochloride

Registration Number: NCT01176565

Lead Sponsor: University of Minnesota

Brief 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1000

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard SBP Reduction Arm	Intravenous nicardipine hydrochloride	Intravenous nicardipine hydrochloride will be used as necessary (pro re nata or "PRN") as the primary agent in lowering SBP. The goal for the standard BP reduction group will be to reduce and maintain SBP \< 180 mmHg for 24 hours from randomization. 160 mmHg is the target SBP for this arm. For the standard group, SBP below the assigned treatment range is not artificially elevated to stay within the range if lower SBP occurs with nicardipine turned off (no fluid bolus given unless SBP falls below 110 mmHg with nicardipine off and there is risk for hypotension). Euvolemic fluid maintenance is encouraged for all patients according to their medical needs, which may differ.
Intensive SBP Reduction Arm	Intravenous nicardipine hydrochloride	Intravenous nicardipine hydrochloride will be used as necessary (pro re nata or "PRN") as the primary agent in lowering SBP. The goal for the intensive BP reduction group will be to reduce and maintain SBP \< 140 mmHg for 24 hours from randomization. 125 mmHg is the target SBP for this arm. For the intensive group, SBP falling below 110 mmHg (lower limit of the assigned treatment range) with nicardipine off is treated with normal saline fluid bolus to prevent or remedy hypotension. Euvolemic fluid maintenance is encouraged for all patients according to their medical needs, which may differ.

Primary Outcome Measures

Name	Time	Method
Death or Disability According to Modified Rankin Scale Score at 90 Days (3 Months) From Randomization	90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization	The primary outcome was death or disability, defined by modified Rankin scale (mRS) of 4-6 at 90 days following treatment. The modified Rankin Scale score ranges from 0, indicating no symptoms, to 6, indicating death. A score of 4 indicates moderately severe disability including the inability to walk or attend to one's own bodily needs. A score of 5 indicates severe disability; bedridden, incontinent, and requiring constant nursing care. To score a 3 or lower on the mRS, a person must at least be able to walk without the assistance of another person. We chose the mRS because of its high inter-observer reliability, superiority to other indices, and consistency with previous trials in patients with ICH. Reliability was further increased by use of a structured interview template and by requiring mRS assessors to pass a certification test. Persons conducting the 90-day mRS assessment were to be unaware of the treatment arm or clinical course of the patients they assessed.

Secondary Outcome Measures

Name	Time	Method
Hematoma Expansion (Number of Patients With Hematoma Expansion of 33% or Greater Between the Baseline and 24 +/- 6 Hours Head CTs, as Measured by the Central Reader for Patients With Readable Scans for Both Time Points Submitted by Data Lock.)	From the baseline head CT to the 24 +/- 6 hours from randomization head CT	Hematoma expansion as determined by serial CT scans: Hematoma expansion was defined as an increase in the volume of intraparenchymal hemorrhage of 33% or greater as measured by a central imaging analyst who was was unaware of the treatment assignments, clinical findings, and time points of image acquisition. The area of the hematoma was delineated by image analysis software with the use of density thresholds on each slice, followed by manual correction. To ensure accuracy and consistency of the readings, images were coded randomly and independently of subject numbers and manual correction was also done without awareness of treatment assignments, clinical findings, or time points of image acquisition. This data point is defined as being present (hematoma expansion of 33% or more was calculated between the baseline scan hematoma volume and the 24 +/- 6 hours hematoma volume measures at data analysis), meaning that hematoma expansion as defined must have occurred or it was not counted.
Quality of Life at 90 Days Using EuroQol (EQ) Measures: EQ-5D (EuroQol Five Dimension), Consisting of Standardized EQ-5D-3L (EuroQol Five Dimension, Three-Level) Questionnaire and EQ VAS (EuroQol Visual Analog Scale) Scores	90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization	Standardized scales developed by the EuroQol Research Foundation were used as a secondary outcome measure in addition to the mRS scale score. The EQ-5D is a simple, standardized non-disease-specific instrument for describing and valuating health-related quality of life. The EQ-5D-3L questionnaire consists of 5 questions in 5 different domains and allows for responses from 1 (the best outcome) to 3 (the worst outcome) in each of five categories (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Total scores range from 5 to 15, with lower scores indicating better quality of life and a higher score indicating a worse quality of life. A second component of EuroQol outcome measurements is a printed 20 cm visual analogue scale (EQ VAS) that appears somewhat like a thermometer, on which a score from 0 (worst imaginable health state or death) to 100 (best imaginable health state) is marked by the patient (or, when necessary, their proxy) with the scale in view.

Trial Locations

Locations (171): Brigham & Women's Hospital
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Boston, Massachusetts, United States
Boston Medical Center
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Boston, Massachusetts, United States
Banner University Medical Center - South Campus
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Tuscon, Arizona, United States
Santa Clara Valley Medical Center
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Santa Clara, California, United States
Colorado Neurological Institute
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Englewood, Colorado, United States
Mayo Clinic - Jacksonville
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Jacksonville, Florida, United States
OSF Saint Francis Medical Center
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Peoria, Illinois, United States
Southern Illinois University Memorial Medical Center
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Springfield, Illinois, United States
Lutheran Hospital Indiana
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Fort Wayne, Indiana, United States
Massachusetts General Hospital
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Boston, Massachusetts, United States
Allegiance Health
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Jackson, Michigan, United States
University Hospitals Case Medical Center
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Cleveland, Ohio, United States
University of Pennsylvania
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Philadelphia, Pennsylvania, United States
Temple University
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Philadelphia, Pennsylvania, United States
UPMC-Mercy Hospital
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Pittsburgh, Pennsylvania, United States
Reading Hospital
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West Reading, Pennsylvania, United States
Texas Tech University Health Sciences Center
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El Paso, Texas, United States
The First Hospital of Shanxi Medical University
🇨🇳
Taiyuan City, China
University of Bonn
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Bonn, Germany
University Hospital Dresden
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Dresden, Germany
Baylor College of Medicine - St. Luke's Episcopal Hospital
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Houston, Texas, United States
Chonnam National University Hospital
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Gwangju, Korea, Republic of
Seoul National University Hospital
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Seoul, Korea, Republic of
Seoul National University Boramae Hospital
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Seoul, Korea, Republic of
Changhua Christian Hospital
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Changhua, Taiwan
Hennepin County Medical Center
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Minneapolis, Minnesota, United States
University of Texas Health Science Center at San Antonio
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San Antonio, Texas, United States
The Second Hospital of Hebei Medical University
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Shijiazhuang City, Hebei, China
Kansas University Medical Center
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Kansas City, Kansas, United States
Maricopa Medical Center
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Phoenix, Arizona, United States
Vanderbilt Stroke Center
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Nashville, Tennessee, United States
Wayne State University - Detroit Receiving Hospital
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Detroit, Michigan, United States
Henry Ford Health System
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Detroit, Michigan, United States
Sinai-Grace Hospital
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Detroit, Michigan, United States
Oklahoma University Health Sciences Center (OUHSC)
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Oklahoma City, Oklahoma, United States
North Shore University Hospital
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Manhasset, New York, United States
New Jersey Neuroscience Institute, JFK Medical Center
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Edison, New Jersey, United States
Banner University Medical Center - University Campus
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Tuscon, Arizona, United States
Tulane Medical Center
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New Orleans, Louisiana, United States
Rochester General Hospital
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Rochester, New York, United States
Cooper University Hospital
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Camden, New Jersey, United States
St. Joseph's Regional Medical Center
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Clifton, New Jersey, United States
Christiana Hospital
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Newark, Delaware, United States
West Jefferson Medical Center
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Marrero, Louisiana, United States
Louisiana State University Health Sciences Center, Shreveport
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Shreveport, Louisiana, United States
Eastern Idaho Medical Consultants
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Idaho Falls, Idaho, United States
Mayo Clinic Pheonix
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Scottsdale, Arizona, United States
Emory University Hospital
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Atlanta, Georgia, United States
University of Mississippi Medical Center
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Jackson, Mississippi, United States
Hackensack University Medical Center
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Hackensack, New Jersey, United States
Palmetto Health
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Columbia, South Carolina, United States
University of New Mexico
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Albuquerque, New Mexico, United States
Kobe City Medical Center General Hospital
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Kobe City, Japan
Kaohsiung Medical University Hospital
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Kaohsiung, Taiwan
National Taiwan University Hospital
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Taipei, Taiwan
Taipei Veteran's Hospital
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Taipei, Taiwan
Nagoya Medical Center
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Nagoya City, Aichi, Japan
Keio University Hospital
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Tokyo, Japan
Kaohsiung Veterans General Hospital
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Kaohsiung City, Taiwan
National Cheng Kung University Hospital
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Tainan, Taiwan
University of Alberta
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Edmonton, Alberta, Canada
West Virginia University - Ruby Memorial Hospital
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Morgantown, West Virginia, United States
Abington Memorial Hospital
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Abington, Pennsylvania, United States
Saiseikai Kumamoto Hospital
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Kumamoto City, Kumamoto, Japan
Kyushu Medical Center
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Fukuoka, Japan
Toranomon Hospital
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Tokyo, Japan
Montreal Neurological Institute and Hospital
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Montreal, Quebec, Canada
Saiseikai Yokohamashi Tobu Hospital
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Kanagawa, Kanagowa, Japan
National Cerebral and Cardiovascular Center
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Osaka, Japan
Kawasaki Medical School
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Okayama, Japan
Kyorin University
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Tokyo, Japan
China Medical University Hospital
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Taichung, Taiwan
Tri-Service General Hospital
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Taipei, Taiwan
Shin-Kong Wu Ho-Su Memorial Hospital
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Taipei, Taiwan
UAB Comprehensive Stroke Center
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Birmingham, Alabama, United States
University of South Florida, Tampa General Hospital
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Tampa, Florida, United States
Providence Brain and Spine Institute
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Portland, Oregon, United States
Aurora St. Luke's Medical Center
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Milwaukee, Wisconsin, United States
William Beaumont Hospital
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Royal Oak, Michigan, United States
Hoag Memorial Hospital Presbyterian
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Newport Beach, California, United States
Medical College of Wisconsin
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Milwakee, Wisconsin, United States
Ronald Regan UCLA Medical Center
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Los Angeles, California, United States
Long Beach Memorial Medical Center
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Long Beach, California, United States
Community Regional Medical Center of Fresno
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Fresno, California, United States
UCSF Medical Center
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San Francisco, California, United States
Stanford University
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Palo Alto, California, United States
Baptist Medical Center Jacksonville
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Jacksonville, Florida, United States
Loyola University Medical Center
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Maywood, Illinois, United States
Grady Memorial Hospital
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Atlanta, Georgia, United States
Advocate Christ Medical Center
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Oak Lawn, Illinois, United States
Emory University Hospital Midtown
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Atlanta, Georgia, United States
Parkview Hospital
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Fort Wayne, Indiana, United States
St. Cloud Hospital
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St. Cloud, Minnesota, United States
Essentia Health St. Mary's Medical Center
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Duluth, Minnesota, United States
Fairview Southdale Hospital
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Edina, Minnesota, United States
Regions Hospital
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St.Paul, Minnesota, United States
New York City Health and Hospitals Corp. / Kings County Hospital
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Brooklyn, New York, United States
Mamoides Medical Center
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Brooklyn, New York, United States
Sister of Charity/Buffalo Mercy Hospital, Catholic Health System
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Buffalo, New York, United States
Columbia University
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New York, New York, United States
UHS Wilson Medical Center
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Johnson City, New York, United States
SUNY Downstate
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New York, New York, United States
Mission Hospital
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Asheville, North Carolina, United States
Strong Stroke Center
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Rochester, New York, United States
Lincoln Medical and Mental Health Center
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New York, New York, United States
Akron General Hospital
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Akron, Ohio, United States
University of Toledo Medical Center
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Toledo, Ohio, United States
Vidant Medical Center
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Greenville, North Carolina, United States
Guilford Neurologic Associates
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Greenboro, North Carolina, United States
Lehigh Valley Health Network
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Allentown, Pennsylvania, United States
Ohio State University - Wexner Medical Center
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Columbus, Ohio, United States
Geisinger Medical Center
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Danville, Pennsylvania, United States
Penn State Univ/ Hershey Med Center
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Hershey, Pennsylvania, United States
Hahnemann University Hospital
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Philadelphia, Pennsylvania, United States
UPMC Presbyterian Hospital
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Pittsburgh, Pennsylvania, United States
Wellspan York Hospital
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York, Pennsylvania, United States
UT Southwestern - Parkland Hospital
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Dallas, Texas, United States
Memorial Herman - Texas Medical Center
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Houston, Texas, United States
Baylor College of Medicine - Ben Taub Community Hospital
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Houston, Texas, United States
Methodist Hospital - The Neurological Institute
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Houston, Texas, United States
Valley Baptist Medical Center
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Harlingen, Texas, United States
Intermountain Medical Center
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Murray, Utah, United States
Baotou Central Hospital
🇨🇳
Baotou, China
Datong Third People's Hospital
🇨🇳
Datong, China
The Second Hospital of Shanxi Medical University
🇨🇳
Taiyuan City, Shanxi, China
Wuhan Brain Hospital
🇨🇳
Wuhan, China
Renmin Hospital of Wuhan University
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Wuhan, China
University Hospital Leipzig
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Leipzig, Germany
Beijing Tiantan Hospital
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Beijing, China
The First People's Hospital of Taizhou
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Taizhou City, China
Peking University Third Hospital
🇨🇳
Beijing, China
Tianjin Fourth Central Hospital
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Tianjin, China
People's Hopital of Zhengzhou
🇨🇳
Zhengzhou, China
Charité Universtity Medicine Berlin
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Berlin, Germany
Clinic Frankfurt Hoechst
🇩🇪
Frankfurt, Germany
University Hospital Mannheim
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Mannheim, Germany
University Hospital Heidelberg
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Heidelberg, Germany
University of Tubingen
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Tubingen, Germany
University Hospital Halle
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Halle (Saale), Germany
St. Marianna - Toyoko
🇯🇵
Kawasaki, Japan
University Hospital Meunster
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Munster, Germany
Nakamura Memorial Hospital
🇯🇵
Sapporo, Hokkaido, Japan
St. Marianna University Hospital
🇯🇵
Kawasaki, Japan
Gifu University Hospital
🇯🇵
Gifu, Japan
Kyung Hee University Hospital
🇰🇷
Seoul, Korea, Republic of
Kohnan Hospital
🇯🇵
Sendai, Japan
Saiseikai Central Hospital - Tokyo
🇯🇵
Tokyo, Japan
Seoul National University Bundang Hospital
🇰🇷
Seongnam, Gyeonggi, Korea, Republic of
Taichung Veterans General Hopital
🇨🇳
Taichung City, Taiwan
Sutter Roseville Medical Center
🇺🇸
Roseville, California, United States
Good Samaritan Hospital
🇺🇸
San Jose, California, United States
UC Davis Medical Center
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Sacramento, California, United States
Novant Clinical Research Institute/Forsyth Medical Center
🇺🇸
Winston-Salem, North Carolina, United States
Wake Forest Baptist Medical Center (Wake Forest School of Medicine)
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Winston-Salem, North Carolina, United States
Saint Louis University
🇺🇸
Saint Louis, Missouri, United States
Yale - New Haven Hospital
🇺🇸
New Haven, Connecticut, United States
University of Louisville
🇺🇸
Louisville, Kentucky, United States
Saint Luke's Neuroscience Institute
🇺🇸
Kansas City, Missouri, United States
Research Medical Center
🇺🇸
Kansas City, Missouri, United States
University of Florida Gainesville
🇺🇸
Gainesville, Florida, United States
Interim LSU Hospital
🇺🇸
New Orleans, Louisiana, United States
Ochsner Clinic Foundation
🇺🇸
New Orleans, Louisiana, United States
Seton Medical Center Austin
🇺🇸
Austin, Texas, United States
St. David's Medical Center
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Austin, Texas, United States
University Medical Center Brackenridge
🇺🇸
Austin, Texas, United States
Virginia Commonwealth University Medical Center
🇺🇸
Richmond, Virginia, United States
University of Kentucky
🇺🇸
Lexington, Kentucky, United States
University of California San Diego
🇺🇸
La Jolla, California, United States
Maine Medical Center
🇺🇸
South Portland, Maine, United States
Thomas Jefferson University
🇺🇸
Philadelphia, Pennsylvania, United States
Rhode Island Hospital
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Providence, Rhode Island, United States