Clinical Trial: Antihypertensive Treatment of Acute Cerebral Hemorrhage-II

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-II: A Phase III Randomized Multicenter Clinical Trial of Blood Pressure Reduction for Hypertension in Acute

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 Summary: 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 pr
Sponsor: University of Minnesota - Clinical and Translational Science Institute

Current Primary Outcome: Death or Disability According to Modified Rankin Scale Score at 90 Days (3 Months) From Randomization [ Time Frame: 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.


Original Primary Outcome: A pragmatic, streamlined randomized design to evaluate the efficacy of intensive SBP reduction and its effect on outcomes measures at 24 h and at 3 m from randomization in subjects with ICH [ Time Frame: August, 2010- July 2015 ]

Primary outcome is death or disability, defined by modified Rankin scale (mRS) of 4-6 at 3 m following treatment. We chose the mRS because of its high inter-observer reliability, superiority to other indices (e.g., Barthel index), and consistency with previous trials in patients with ICH. Further reliability will be increased by training raters in using the structured interview and obtaining a mRS grade. A dichotomous outcome was chosen to reduce the rate of misclassification and increase the sensitivity of detecting meaningful difference.


Current Secondary Outcome:

  • 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 [ Time Frame: 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.
  • 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.) [ Time Frame: 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.


Original Secondary Outcome: Secondary Outcomes [ Time Frame: August, 2010- July 2015 ]

EuroQOL: EuroQOL, is a simple, standardized non-disease-specific instrument for describing and valuating health-related quality of life. Its components are a printed 'thermometer'-type visual analogue scale and EQ-5D, which consists of 5 questions in 5 different domains and allows for responses from 1 (the best outcome) to 3 (the worst).

Hematoma expansion as determined by serial CT scans: Hematoma expansion will be defined as an increase in the volume of intraparenchymal hemorrhage of >33% as measured by image analysis on the 24-h CT compared with the baseline CT scan.



Information By: University of Minnesota - Clinical and Translational Science Institute

Dates:
Date Received: August 4, 2010
Date Started: May 15, 2011
Date Completion:
Last Updated: March 13, 2017
Last Verified: March 2017