Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-II: A Phase III Randomized Multicenter Clinical Trial of Blood Pressure Reduction for Hypertension in Acute Intracerebral Hemorrhage
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 1,000
- 试验地点
- 171
- 主要终点
- Death or Disability According to Modified Rankin Scale Score at 90 Days (3 Months) From Randomization
研究概览
简要总结
The specific aims of this study are to:
- 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.
- 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.
- 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.
- 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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Standard SBP Reduction Arm
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.
干预措施: Intravenous nicardipine hydrochloride (Drug)
Intensive SBP Reduction Arm
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.
干预措施: Intravenous nicardipine hydrochloride (Drug)
结局指标
主要结局
Death or Disability According to Modified Rankin Scale Score at 90 Days (3 Months) From Randomization
时间窗: 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.
次要结局
- 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)
- 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)