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Antihypertensive Treatment of Acute Cerebral Hemorrhage-II (ATACH-II)

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ClinicalTrials.gov Identifier: NCT01176565
Recruitment Status : Terminated (Planned interim analysis: no significant outcome differences between groups)
First Posted : August 6, 2010
Results First Posted : April 25, 2017
Last Update Posted : April 25, 2017
Sponsor:
Collaborators:
National Institute of Neurological Disorders and Stroke (NINDS)
Medical University of South Carolina
Johns Hopkins University
University of Michigan
Neurocritical Care Research Network
National Cerebral and Cardiovascular Center
Japan Cardiovascular Research Foundation
Beijing Tiantan Hospital
China Medical University Hospital
University Hospital Heidelberg
Seoul National University Hospital
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Intracerebral Hemorrhage
Intervention Drug: Intravenous nicardipine hydrochloride
Enrollment 1000

Recruitment Details A total of 8,532 patients who presented to enrolling sites for emergency care within 6 hours of symptom onset and were found to have non-traumatic intracerebral hemorrhage (ICH) on head CT imaging were screened for eligibility beginning January 7, 2011. A total of 1000 patients were enrolled in the trial between May 15, 2011 and September 14, 2015.
Pre-assignment Details Consent for participation was obtained from the patient or their allowable representative prior to randomization. All patients randomized were considered as enrolled. Treatment to lower systolic blood pressure (SBP) to the assigned range had to begin within 4.5 hours from symptom onset. Treatment for elevated SBP was not delayed for randomization.
Arm/Group Title Standard SBP Reduction Arm Intensive SBP Reduction Arm
Hide Arm/Group Description

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: 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 was greater then the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

Period Title: Overall Study
Started 500 500
Completed 480 481
Not Completed 20 19
Reason Not Completed
Lost to Follow-up             12             16
Withdrawal by Subject             7             1
Not Analyzed (any other reason)             1             2
Arm/Group Title Standard SBP Reduction Arm Intensive SBP Reduction Arm Total
Hide Arm/Group Description

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

Total of all reporting groups
Overall Number of Baseline Participants 500 500 1000
Hide Baseline Analysis Population Description
Subjects were randomized to standard vs. intensive SBP control. Below-range SBP was not artifically elevated in the standard SBP reduction arm; euvolemic fluid balance was maintained but spontaneous recovery was not prevented. For below-range SBP in the intensive SBP control arm, nicardipine was discontinued and if needed IV fluid bolus was given.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 500 participants 500 participants 1000 participants
61.9  (13.1) 62  (13.1) 61.93  (13.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
Female
184
  36.8%
196
  39.2%
380
  38.0%
Male
316
  63.2%
304
  60.8%
620
  62.0%
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
Hispanic or Latino
41
   8.2%
38
   7.6%
79
   7.9%
Not Hispanic or Latino
446
  89.2%
446
  89.2%
892
  89.2%
Unknown or Not Reported
13
   2.6%
16
   3.2%
29
   2.9%
[1]
Measure Description:

Ethnicity describes persons who have (versus have not) self-identified as being of Cuban, Mexican, Puerto Rican, Cuban, South or Central American, or other Spanish culture or origin, regardless of race.

Data are analyzed according to the ethnicity and race of patients included to determine whether there are population differences in health measures or treatment responses that differ. Whether recruitment included an adequate diversity within the affected population is important to understanding the generalizability of results that were obtained and whether further research may be indicated.

Race/Ethnicity, Customized   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Race Number Analyzed 500 participants 500 participants 1000 participants
Asian
285
  57.0%
277
  55.4%
562
  56.2%
Black
58
  11.6%
73
  14.6%
131
  13.1%
White
145
  29.0%
142
  28.4%
287
  28.7%
Other or unknown
12
   2.4%
8
   1.6%
20
   2.0%
[1]
Measure Description: Race and ethnicity were recorded according to how a person identified themselves, not according to genetic testing or observation. The number of persons who reported American Indian, Alaska Native, Native Hawaiian of other Pacific Islander, or of having origins within more than one race has been included in the "other or unknown" category because the number of persons enrolled in the study from each of these categories was too small to provide a meaningful analysis that would examine these groups individually. Asian race included patients enrolled in Asian countries and non-Asian countries.
Recruited at site in Asia   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
273
  54.6%
264
  52.8%
537
  53.7%
[1]
Measure Description: Defined as patients who were enrolled at a clinical site geographically located within regions including Japan, China, Taiwan, or South Korea. Data from these patients were analyzed separately in addition to being part of the full group and other race/ethnicity analyses to examine for potential population differences surrounding intracerebral hemorrhage (ICH) events and recovery that are regional in nature.
First Glasgow Coma Scale Score assessed upon hospital emergency department (ED) arrival   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
ED arrival GCS score = 3 - 11
74
  14.8%
73
  14.6%
147
  14.7%
ED arrival GCS score = 12 - 14
142
  28.4%
152
  30.4%
294
  29.4%
ED arrival GCS score = 15
284
  56.8%
275
  55.0%
559
  55.9%
[1]
Measure Description: The Glasgow Coma Scale (GCS) score is a measure of level of consciousness. The scale quantifies response in three components: eye, motor, and verbal. A lower score indicates a reduced response and a higher score indicates a full response. At least one point is given in each category so the scale ranges from 3 to 15. A score of 3 indicates deep unconsciousness; a higher score indicates milder impairment of consciousness. The maximum score of 15 indicates consciousness is not impaired but other neurological symptoms may still be present. Estimated verbal scoring was used for intubated patients.
Systolic Blood Pressure at presentation in hospital emergency department (ED)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  mmHg
Number Analyzed 499 participants 500 participants 999 participants
201.1  (26.9) 200  (27.1) 200.6  (27.0)
[1]
Measure Description: Blood pressure is reported as the systolic (systolic blood pressure or "SBP") reading "over" the diastolic (or DBP) reading, and is measured in millimeters of mercury (mmHg) on a gauge. SBP is a measure of the force pressing against the blood vessels when the heart contracts to push blood out to the body, and was considered most important for this study. DBP measures lingering pressure within the blood vessels as the heart fills with newly-oxygenated blood from the lungs. Hospitals selected the method that they felt was the most accurate way to report systolic blood pressures for each patient.
[2]
Measure Analysis Population Description: Data were missing for 1 patient in the standard-treatment group. It was permissible for pre-arrival or post-admission qualifying SBP to be used in eligibility determination if all other criteria were met.
Median NIHSS score (range)   [1] 
Median (Full Range)
Unit of measure:  Units on a scale (NIHSS range 0 - 42)
Number Analyzed 500 participants 500 participants 1000 participants
11
(0 to 40)
11
(0 to 40)
11
(0 to 40)
[1]
Measure Description: The National Institutes of Health Stroke Scale (NIHSS) is a serial measure of neurologic deficit (problems in function). It uses a scale (range 0 - 42) to quantify neurologic deficits in 11 categories. The categories are measured by asking questions that indicate the patient's level of consciousness, then testing horizontal eye movements, visual fields, facial palsy, movement in each limb, sensation, language and speech, and extinction or inattention on one side of the body. A score of 0 indicates normal function without neurologic deficit. Higher scores indicate greater severity of deficit.
Intracerebral Hematoma Volume   [1] [2] 
Median (Full Range)
Unit of measure:  Cubic centimeters (cm3)
Number Analyzed 492 participants 496 participants 988 participants
10.2
(0.98 to 79.1)
10.3
(2.3 to 85.2)
10.3
(0.98 to 85.2)
[1]
Measure Description: Hematoma volumes are reported in cubic centimeters (cm3), as measured by the central reader. The area of the hematoma on head CT imaging was delineated by image analysis software with the use of density thresholds on each slice, followed by manual correction. The central reader and those performing manual correction were unaware of the patient identities, treatment assignments, clinical findings, and time points of image acquisition. The software provided total volume measurements by summing up volumes (product of area and slice thickness) from all the slices containing the hematoma.
[2]
Measure Analysis Population Description: A precise measure of bleeding within the brain was occasionally unable to be determined or baseline imaging wasn't submitted for analysis before data lock. This measure was missing for 8 patients in the standard treatment group and 4 in the intensive group. For eligibility, hematoma volume was estimated rapidly in 3 dimensions (ABC/2) at bedside.
Intracerebral hematoma volume greater than 30 cm3   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 492 participants 496 participants 988 participants
51
  10.4%
45
   9.1%
96
   9.7%
[1]
Measure Description: Hematoma volumes are reported in cubic centimeters (cm3), as measured by the central reader. The area of the hematoma on head CT imaging was delineated by image analysis software with the use of density thresholds on each slice, followed by manual correction. The central reader and those performing manual correction were unaware of the patient identities, treatment assignments, clinical findings, and time points of image acquisition. The software provided total volume measurements by summing up volumes (product of area and slice thickness) from all the slices containing the hematoma.
[2]
Measure Analysis Population Description: A precise measure of bleeding within the brain was occasionally unable to be determined or baseline imaging wasn't submitted for analysis before data lock. This measure was missing for 8 patients in the standard treatment group and 4 in the intensive group. For eligibility, hematoma volume was estimated rapidly in 3 dimensions (ABC/2) at bedside.
Intraventricular Hemorrhage   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 492 participants 496 participants 988 participants
142
  28.9%
122
  24.6%
264
  26.7%
[1]
Measure Description: Intraventricular hemorrhage is bleeding that is present within the ventricles, or internal fluid-filled spaces, within the brain. These spaces are usually filled with cerebrospinal fluid that also circulates around the brain and spinal column, which helps to protect and cushion the delicate brain tissue. In this study, when intraventricular hemorrhage was present it meant that bleeding had extended from another region within the brain tissue to also being present in the brain ventricles. Intraventricular blood is associated with other complications and may indicate a more severe condition.
[2]
Measure Analysis Population Description: The presence of blood within a brain ventricle as opposed to the hematoma (blood clot) within surrounding brain tissue pressing in to the ventricular space occasionally can't be determined, or baseline imaging wasn't submitted for analysis. This measure was missing for 8 patients in the standard treatment group and 4 in the intensive group.
Location of Hemorrhage   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 492 participants 496 participants 988 participants
Thalamus
180
  36.6%
193
  38.9%
373
  37.8%
Basal ganglia
251
  51.0%
255
  51.4%
506
  51.2%
Cerebral lobe
60
  12.2%
48
   9.7%
108
  10.9%
Cerebellum
1
   0.2%
0
   0.0%
1
   0.1%
[1]
Measure Description: The primary location of hemorrhage (bleeding) in the brain tissue was recorded as being located in the basal ganglia, thalamus, or a lobar region on either the right or left side of the brain. One patient was included that had a cerebellar hemorrhage, which means that bleeding was in the lower dorsal (back) region of the brain.
[2]
Measure Analysis Population Description: The primary location of bleeding within the brain is occasionally unable to be clearly determined, or baseline imaging wasn't submitted for analysis. This measure was missing for 8 patients in the standard treatment group and 4 in the intensive group.
Prior stroke/transient ischemic attack  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
84
  16.8%
80
  16.0%
164
  16.4%
Other prior nervous system disorders  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
17
   3.4%
23
   4.6%
40
   4.0%
History of congestive heart failure  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
21
   4.2%
16
   3.2%
37
   3.7%
History of atrial fibrillation  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
16
   3.2%
20
   4.0%
36
   3.6%
Myocardial infarction in the previous 3 months  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
0
   0.0%
1
   0.2%
1
   0.1%
History of coronary artery disease  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
17
   3.4%
27
   5.4%
44
   4.4%
History of hypertension  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
382
  76.4%
411
  82.2%
793
  79.3%
History of peripheral vascular disease  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
13
   2.6%
9
   1.8%
22
   2.2%
History of hyperlipidemia  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
119
  23.8%
122
  24.4%
241
  24.1%
History of cardiac dysrhythmias  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
21
   4.2%
17
   3.4%
38
   3.8%
History of diabetes mellitus Type 2  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
83
  16.6%
92
  18.4%
175
  17.5%
Previous use of antihypertensive drugs  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
235
  47.0%
260
  52.0%
495
  49.5%
Symptom onset to randomization time, minutes  
Mean (Standard Deviation)
Unit of measure:  Minutes
Number Analyzed 500 participants 500 participants 1000 participants
184.7  (56.7) 182.2  (57.2) 183.5  (57)
Symptom onset to nicardipine infusion time   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Minutes
Number Analyzed 479 participants 497 participants 976 participants
165.3  (101.3) 149  (65) 157  (85.2)
[1]
Measure Description: To qualify, patients had to have SBP greater than 180 mmHg prior to antihypertensive treatment and SBP not below 140 mmHg at the time of randomization. Nicardipine infusion had to be able to start within 4.5 hours of symptom onset. In accordance with recommendations, treatment of significant hypertension in patients presenting with ICH was not delayed for consent and randomization. This measure captures the earliest nicardipine start time but other intravenous antihypertensive medications may have been given before then. "Zero" nicardipine start rates may not have been recorded in all cases.
[2]
Measure Analysis Population Description: Data from 24 (3 intensive and 21 standard arm) patients was missing. If nicardipine wasn't needed to achieve the assigned SBP range at the time of randomization, more common in the standard arm, nicardipine was initiated at zero rate. "Zero rate" IV infusions have less consistent recording. Some patients had SBP within range without nicardipine.
Mean minimum systolic blood pressure, during the first 2 hours post randomization   [1] 
Mean (Standard Deviation)
Unit of measure:  mmHg
Number Analyzed 497 participants 500 participants 997 participants
141.1  (14.8) 128.9  (16) 135  (16.6)
[1]
Measure Analysis Population Description: Data were missing for 3 subjects in the standard treatment arm. If a vasoactive IV drip medication (such as nicardipine) is not in use, then standard-of-care parameters for close monitoring of SBP are different (frequency of required monitoring is less). Patient transfer and some procedures can preclude vigilance in recording research-only SBP.
Failure to attain systolic blood pressure target within 2 hours   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
4
   0.8%
61
  12.2%
65
   6.5%
[1]
Measure Description: Elevation of systolic blood pressure is common with intracerebral hemorrhage. Recovery of normalized blood pressure may occur quickly for some patients and only after an extended time for others, and more or less medication may be needed. The systolic blood pressure goal is usually achieved incrementally, as antihypertensive medication begins to take effect to control blood pressure. A lower target SBP range may take longer or be more difficult to achieve. The goal in this study was to achieve blood pressure control within 2 hours of randomization for all patients, regardless of treatment arm.
Failure to attain systolic blood pressure target for 2 consecutive hours during 2-24 hours   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 500 participants 500 participants 1000 participants
7
   1.4%
78
  15.6%
85
   8.5%
[1]
Measure Description: This data parameter is a measure of the success (or lack of success) with which SBP control to the assigned treatment range was consistently maintained during the 24-hour SBP control study period.
1.Primary Outcome
Title Death or Disability According to Modified Rankin Scale Score at 90 Days (3 Months) From Randomization
Hide Description 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.
Time Frame 90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All subjects were analyzed for known death at any time following randomization. Patients surviving through 90 days (± 14 days per protocol window; data used up to ± 30 days) were assessed for disability using the mRS. Patients not completing the 90-day visit within 30 days of due date aren't included in the death & disability participant counts.
Arm/Group Title Standard SBP Reduction Arm Intensive SBP Reduction Arm
Hide Arm/Group Description:

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

Overall Number of Participants Analyzed 500 500
Measure Type: Count of Participants
Unit of Measure: Participants
Death or disability at 90 days (mRS = 4 - 6)
181
  36.2%
186
  37.2%
Known death at or before 90 days
34
   6.8%
33
   6.6%
2.Secondary Outcome
Title 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
Hide Description 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.
Time Frame 90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All available valid data were analyzed. Outcomes collected outside of 90 ± 30 days weren't considered valid. EQ-5D data were missing for 28 patients in the intensive group & for 27 in the standard group. EQ VAS data were missing for 144 patients in the intensive group and for 146 in the standard group.
Arm/Group Title Standard SBP Reduction Arm Intensive SBP Reduction Arm
Hide Arm/Group Description:

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

Overall Number of Participants Analyzed 473 472
Median (Full Range)
Unit of Measure: units on a scale
EQ-5D utility scale questionnaire Number Analyzed 473 participants 472 participants
0.7
(0 to 1.0)
0.7
(-0.109 to 1.0)
EQ VAS (visual analog scale) Number Analyzed 354 participants 356 participants
70
(0 to 100)
62.5
(0 to 100)
3.Secondary Outcome
Title 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.)
Hide Description 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.
Time Frame From the baseline head CT to the 24 +/- 6 hours from randomization head CT
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants with readable head CTs at baseline and 24 +/- 6 hours from randomization (submitted before data lock) were analyzed. Hematoma expansion was only recorded as present if ≥ 33% volume increase was calculated. Scans done outside of time window + margin, submitted after data lock, or not readable in standard DICOM format could not be used.
Arm/Group Title Standard SBP Reduction Arm Intensive SBP Reduction Arm
Hide Arm/Group Description:

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

Overall Number of Participants Analyzed 426 450
Measure Type: Count of Participants
Unit of Measure: Participants
104
  24.4%
85
  18.9%
4.Other Pre-specified Outcome
Title Neurological Deterioration Within 24 Hours, Defined by a Decrease of 2 or More Points on the GCS Score or an Increase of 4 or More Points on the NIHSS Score From Baseline, Not Related to Sedation or Hypnotic-agent Use and Sustained for at Least 8 Hours.
Hide Description Neurologic deterioration was measured using two scales. The Glasgow Coma Scale (GCS) score measures of level of consciousness in eye, motor, and verbal components. At least one point is given in each category. The scale ranges from 3 to 15, with 3 indicating deep unconsciousness and 15 indicating consciousness is not impaired. The National Institutes of Health Stroke Scale (NIHSS) quantifies neurologic deficits in 11 categories. Level of consciousness, horizontal eye movement, visual fields, facial palsy, movement in each limb, sensation, language & speech, and extinction or inattention on one side of the body are tested. Scores range from 0 to 42, with 0 indicating normal function and higher scores indicating greater deficit severity. Neurological status was checked per ICU standards through 24 hours, recommended as hourly GCS and full assessment every 2 hours. NIHSS assessment at baseline and 24 +/- 3 hours was pre-specified. Assessments were added for suspected neurological change.
Time Frame From randomization through the 24-hour treatment period
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All subjects were assessed for neurological status regularly. Grid-estimated verbal scoring based on eye and motor scores was used for intubated patients so that GCS scores could be compared over time and was consistent across patients.
Arm/Group Title Standard SBP Reduction Arm Intensive SBP Reduction Arm
Hide Arm/Group Description:

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

Overall Number of Participants Analyzed 500 500
Measure Type: Count of Participants
Unit of Measure: Participants
40
   8.0%
55
  11.0%
5.Other Pre-specified Outcome
Title Hypotension Within 72 Hours
Hide Description Hypotension (abnormally low blood pressure) was the most likely adverse event that could be associated with the study treatment, and is the primary basis (risk) on which neurological deterioration or other untoward effects of the study treatment could occur. It is therefore examined as a numerically-measured occurrence in addition to monitoring patients closely for neurological deterioration or other symptoms. Hypotension, when named as an adverse event, was defined as the syndrome of low blood pressure with SBP < 85 mmHg. Instances of hypotension were to be avoided through close monitoring, and administration of fluid bolus for SBP < 110 mmHg. If hypotension did occur, it was to be reversed as quickly as possible through discontinuation of intravenous nicardipine and intravenous fluid administration, which can be accomplished readily in a variety of settings where patients with intracerebral hemorrhage are routinely housed during early hospitalization.
Time Frame From randomization through 72 hours from randomization
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Blood pressure including the potential for hypotension was monitored according to intensive care unit standards for ICH patients during early hospitalization. Blood pressure was monitored more closely during the 24-hour study period and at times when nicardipine (or other/secondary IV antihypertensive medications) were being titrated.
Arm/Group Title Standard SBP Reduction Arm Intensive SBP Reduction Arm
Hide Arm/Group Description:

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

Overall Number of Participants Analyzed 500 500
Measure Type: Count of Participants
Unit of Measure: Participants
3
   0.6%
6
   1.2%
6.Other Pre-specified Outcome
Title Treatment-related Serious Adverse Event Within 72 Hours of Randomization
Hide Description Adverse events (AEs) and serious adverse events (SAEs) were assessed by the site investigators for all patients, including for their potential relatedness to the study treatment. An Independent Oversight Committee (IOC) reviewed and adjudicated all adverse event data. The 72-hours-from-randomization time window was considered the most likely time frame during which treatment-related adverse events or serious adverse events would be observed. Terminology from the Medical Dictionary for Regulatory Activities (MedDRA) and severity criteria from the Common Terminology Criteria for Adverse Events (CTCAE v. 4.03) were used as a basis for reporting adverse events. Serious adverse events are defined as being fatal, life-threatening, resulting in hospitalization or prolonged hospitalization, resulting in disability or congenital anomaly, or requiring intervention to prevent permanent impairment or damage and were required to be reported promptly.
Time Frame From randomization through 72 hours (3 days)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Relatedness is defined by the terms unrelated, unlikely, possibly, probably, or definitely related to the study treatment. Results are entered as the count of participants experiencing any serious adverse event within 72 hours of randomization that was determined by the site investigator to possibly or more have relationship to the study treatment.
Arm/Group Title Standard SBP Reduction Arm Intensive SBP Reduction Arm
Hide Arm/Group Description:

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

Overall Number of Participants Analyzed 500 500
Measure Type: Count of Participants
Unit of Measure: Participants
6
   1.2%
8
   1.6%
7.Other Pre-specified Outcome
Title Any Serious Adverse Event Within the 90-day Study Period
Hide Description The complete count of all subjects who experienced any serious adverse events throughout their participation in the trial was included in this tabulation. Adverse events (AEs) and serious adverse events (SAEs) were assessed by the site investigators for all patients. Potential relatedness to the study treatment was a required reporting element for all adverse events but was not considered in this count. Terminology from the Medical Dictionary for Regulatory Activities (MedDRA) and severity criteria from the Common Terminology Criteria for Adverse Events (CTCAE v. 4.03) were used as a basis for reporting adverse events. Serious adverse events are defined as being fatal, life-threatening, resulting in hospitalization or prolonged hospitalization, resulting in disability or congenital anomaly, or requiring intervention to prevent permanent impairment or damage and were required to be reported promptly. An Independent Oversight Committee (IOC) reviewed and adjudicated adverse event data.
Time Frame From randomization through the 90 day visit (90 ± 14 days per protocol window; up to ± 30 days data is used) or until known death, withdrawal, or loss to follow-up.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Patients may have experienced more than one adverse event. This measure is designed to show the total count of any patients who experienced any type of serious adverse event, whether it was felt to be related to the study treatment or not, throughout the duration of their participation in the study.
Arm/Group Title Standard SBP Reduction Arm Intensive SBP Reduction Arm
Hide Arm/Group Description:

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

Overall Number of Participants Analyzed 500 500
Measure Type: Count of Participants
Unit of Measure: Participants
100
  20.0%
128
  25.6%
Time Frame Adverse events were collected between randomization and the end-of-study visit. All adverse events (defined as abnormal test results, new diagnoses, worsening of conditions, or other health events of clinical significance) were collected through day 7 or hospital discharge, whichever came first. Only serious adverse events (SAEs) were collected from Day 7 (or discharge, if sooner) through final study visits at 3-months +/- 30 days. SAEs, 5-day reporting timeline.
Adverse Event Reporting Description Adverse events during hospitalization: assessed from medical records. Post-hospital discharge, patients/proxy were asked if illness or hospitalization had occurred; available medical records also checked. CTCAE v. 4.03 as severity grading reference. Relatedness of adverse events: assessed by the site investigator within categories unrelated, unlikely, possibly, probably, or definitely related to the study treatment. Analyses by code + related safety groupings. AEs ≩ all subjects being affected.
 
Arm/Group Title Standard SBP Reduction Arm Intensive SBP Reduction Arm
Hide Arm/Group Description

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the standard blood pressure reduction group was to reduce and maintain SBP under 180 mmHg for 24 hours from randomization. The target SBP for this treatment arm was approximately 160 mmHg (the center of the assigned treatment group range of SBP 140-179 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP despite infusion of the maximum nicardipine dose for 30 minutes, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was to be decreased incrementally or was discontinued if SBP fell below the assigned treatment range.

Nicardipine hydrochloride was used according to need as the primary agent in lowering systolic blood pressure (SBP).

The goal for the intensive blood pressure reduction group was to reduce and maintain SBP under 140 mmHg for 24 hours from randomization. The target SBP for this treatment arm was 125 mmHg (the center of the treatment group range SBP 110 - 139 mmHg).

Nicardipine hydrochloride: 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 was greater than the target SBP after infusion of the maximum nicardipine dose for 30 min, a second agent could be used (Labetalol 5-20 mg IV bolus every 15 min; urapidil substituted in countries without labetalol available) for another hour. Nicardipine use was decreased incrementally or was discontinued if SBP fell below the assigned treatment range. Fluid bolus was given if needed for hypotension.

All-Cause Mortality
Standard SBP Reduction Arm Intensive SBP Reduction Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Standard SBP Reduction Arm Intensive SBP Reduction Arm
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   100/500 (20.00%)      128/500 (25.60%)    
Blood and lymphatic system disorders     
Haemorrhagic anaemia  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Leukocytosis  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Cardiac disorders     
Acute coronary syndrome  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Acute myocardial infarction  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Angiopathy  1 [2]  0/500 (0.00%)  0 1/500 (0.20%)  1
Atrial fibrillation  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Bradycardia  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Cardiac arrest  1  2/500 (0.40%)  2 4/500 (0.80%)  4
Cardiac failure  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Cardiac failure acute  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Cardiac failure congestive  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Cardio-respiratory arrest  1  4/500 (0.80%)  4 0/500 (0.00%)  0
Chest pain  1 [3]  2/500 (0.40%)  2 0/500 (0.00%)  0
Hypertension  1 [3]  1/500 (0.20%)  1 3/500 (0.60%)  3
Hypertensive crisis  1 [2]  0/500 (0.00%)  0 1/500 (0.20%)  1
Hypertensive emergency  1 [2]  0/500 (0.00%)  0 1/500 (0.20%)  1
Hypotension  1 [4]  1/500 (0.20%)  1 1/500 (0.20%)  1
Myocardial infarction  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Myocardial ischaemia  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Pulseless electrical activity  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Tachycardia  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain  1  1/500 (0.20%)  2 0/500 (0.00%)  0
Gastrointestinal haemorrhage  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Ileus paralytic  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Necrotising colitis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Pancreatitis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Small intestinal obstruction  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Upper gastrointestinal haemorrhage  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
General disorders     
Asthenia  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Death  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Drug withdrawal syndrome  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Pyrexia  1 [1]  2/500 (0.40%)  2 1/500 (0.20%)  1
Hepatobiliary disorders     
Cholecystitis  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  2
Cholecystitis acute  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Hepatic function abnormal  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Infections and infestations     
Abdominal abscess  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Abscess oral  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Cholecystitis infective  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Clostridial infection  1 [1]  1/500 (0.20%)  1 1/500 (0.20%)  1
Device related infection  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Enteritis infectious  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Lung infection  1 [1]  2/500 (0.40%)  2 0/500 (0.00%)  0
Meningitis  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Pneumonia  1 [1]  5/500 (1.00%)  5 9/500 (1.80%)  9
Pneumonia staphylococcal  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Sepsis  1  4/500 (0.80%)  4 1/500 (0.20%)  1
Septic shock  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Urinary tract infection  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Urosepsis  1  0/500 (0.00%)  0 3/500 (0.60%)  3
Injury, poisoning and procedural complications     
Brain herniation  1  2/500 (0.40%)  2 2/500 (0.40%)  2
Extradural haematoma  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Fall  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Femoral neck fracture  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Femur fracture  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Pneumothorax traumatic  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Subdural haematoma  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Investigations     
Cyst aspiration  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Liver function test abnormal  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Oxygen saturation decreased  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Respiratory rate increased  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Metabolism and nutrition disorders     
Dehydration  1  1/500 (0.20%)  1 2/500 (0.40%)  2
Hyperkalaemia  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Hyponatraemia  1 [1]  1/500 (0.20%)  1 1/500 (0.20%)  1
Musculoskeletal and connective tissue disorders     
Back pain  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Bladder cancer  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Breast cancer  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Metastasis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Rectal cancer  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Nervous system disorders     
Aphasia  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Brain oedema  1  2/500 (0.40%)  2 3/500 (0.60%)  3
CNS ventriculitis  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Cerebral haematoma  1  6/500 (1.20%)  6 1/500 (0.20%)  1
Cerebral haemorrhage  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Cerebrovascular accident  1  19/500 (3.80%)  19 17/500 (3.40%)  17
Cerebrovascular disorder  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Convulsion  1 [1]  3/500 (0.60%)  3 1/500 (0.20%)  1
Depressed level of consciousness  1 [1]  0/500 (0.00%)  0 2/500 (0.40%)  2
Embolic cerebral infarction  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Embolic stroke  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Epilepsy  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Haemorrhage intracranial  1 [1]  3/500 (0.60%)  3 3/500 (0.60%)  3
Haemorrhagic infarction  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Haemorrhagic stroke  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Hemiplegia  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Hydrocephalus  1 [1]  4/500 (0.80%)  4 7/500 (1.40%)  7
Hypoaesthesia  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Intracranial pressure increased  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  2
Ischaemia  1 [5]  1/500 (0.20%)  1 0/500 (0.00%)  0
Ischaemic cerebral infarction  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Ischaemic stroke  1  2/500 (0.40%)  2 2/500 (0.40%)  2
Mental impairment  1 [1]  1/500 (0.20%)  1 2/500 (0.40%)  2
Mental status changes  1 [1]  2/500 (0.40%)  2 0/500 (0.00%)  0
Neurological decompensation  1 [1]  9/500 (1.80%)  9 18/500 (3.60%)  18
Paraesthesia  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Partial seizures  1 [1]  1/500 (0.20%)  1 1/500 (0.20%)  1
Somnolence  1 [1]  1/500 (0.20%)  1 1/500 (0.20%)  1
Stroke in evolution  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Subdural hygroma  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Syncope  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Transient ischaemic attack  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Psychiatric disorders     
Alcohol withdrawal syndrome  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Depression  1 [1]  1/500 (0.20%)  1 1/500 (0.20%)  1
Schizophrenia, paranoid type  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Renal and urinary disorders     
Blood creatinine increased  1 [6]  1/500 (0.20%)  1 0/500 (0.00%)  0
Haematuria  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Renal failure  1 [1]  1/500 (0.20%)  1 1/500 (0.20%)  1
Renal failure acute  1 [1]  2/500 (0.40%)  2 4/500 (0.80%)  4
Renal failure chronic  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Ureteric obstruction  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Urethral stenosis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Acute respiratory failure  1  4/500 (0.80%)  4 0/500 (0.00%)  0
Aspiration  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Chronic obstructive pulmonary disease  1  0/500 (0.00%)  0 3/500 (0.60%)  4
Dyspnoea  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Hypoxia  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Pleural effusion  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Pneumonia aspiration  1 [1]  5/500 (1.00%)  5 9/500 (1.80%)  9
Pulmonary embolism  1  3/500 (0.60%)  3 4/500 (0.80%)  4
Pulmonary oedema  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Respiratory arrest  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Respiratory distress  1 [1]  1/500 (0.20%)  1 2/500 (0.40%)  2
Respiratory failure  1 [1]  8/500 (1.60%)  8 10/500 (2.00%)  10
Skin and subcutaneous tissue disorders     
Angioedema  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Drug eruption  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Surgical and medical procedures     
Cranioplasty  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Subdural haematoma evacuation  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Vascular disorders     
Arteriovenous fistula  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Circulatory collapse  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Deep vein thrombosis  1 [1]  4/500 (0.80%)  4 3/500 (0.60%)  3
Haemorrhage  1 [1]  2/500 (0.40%)  2 1/500 (0.20%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (Unspecified)
[1]
(Meeting SAE criteria)
[2]
Coded under vascular disorders, also analyzed with cardiac disorders for safety
[3]
(Meeting SAE criteria); coded under general disorders, also analyzed with cardiac disorders for safety
[4]
(Meeting SAE criteria); coded under vascular disorders, also analyzed with cardiac disorders for safety
[5]
Coded under vascular disorders, also analyzed with brain infarct/nervous disorders for safety
[6]
Coded under investigations, also analyzed with renal disorders for safety
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Standard SBP Reduction Arm Intensive SBP Reduction Arm
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   500/500 (100.00%)      500/500 (100.00%)    
Blood and lymphatic system disorders     
Anaemia  1  5/500 (1.00%)  5 9/500 (1.80%)  9
Haemorrhagic anaemia  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Leukocytosis  1 [1]  2/500 (0.40%)  2 12/500 (2.40%)  12
Leukopenia  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Thrombocytopenia  1  4/500 (0.80%)  4 1/500 (0.20%)  1
Cardiac disorders     
Acute myocardial infarction  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Aortic stenosis  1 [2]  0/500 (0.00%)  0 1/500 (0.20%)  1
Atrial fibrillation  1 [1]  2/500 (0.40%)  2 6/500 (1.20%)  7
Atrioventricular block complete  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Atrioventricular block second degree  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Blood pressure decreased  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Blood pressure diastolic increased  1 [3]  1/500 (0.20%)  1 0/500 (0.00%)  0
Blood pressure increased  1 [3]  1/500 (0.20%)  1 0/500 (0.00%)  0
Bradycardia  1 [1]  5/500 (1.00%)  5 1/500 (0.20%)  1
Bundle branch block left  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Cardiac failure  1 [1]  0/500 (0.00%)  0 2/500 (0.40%)  2
Cardiac failure congestive  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Cardiac murmur  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Cardiopulmonary failure  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Chest discomfort  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Chest pain  1 [4]  2/500 (0.40%)  2 3/500 (0.60%)  3
Diastolic dysfunction  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Electrocardiogram ST segment depression  1 [3]  1/500 (0.20%)  1 0/500 (0.00%)  0
Extrasystoles  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Hypertension  1 [5]  5/500 (1.00%)  6 3/500 (0.60%)  3
Hypotension  1 [5]  3/500 (0.60%)  3 6/500 (1.20%)  6
Left ventricular hypertrophy  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Myocardial infarction  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Sinus bradycardia  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Sinus tachycardia  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Supraventricular tachycardia  1  0/500 (0.00%)  0 3/500 (0.60%)  3
Tachycardia  1 [1]  7/500 (1.40%)  7 8/500 (1.60%)  9
Troponin I increased  1  2/500 (0.40%)  3 1/500 (0.20%)  1
Troponin increased  1  3/500 (0.60%)  3 6/500 (1.20%)  7
Ventricular extrasystoles  1  1/500 (0.20%)  1 3/500 (0.60%)  3
Ventricular hypertrophy  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Ventricular tachycardia  1  0/500 (0.00%)  0 3/500 (0.60%)  3
Ear and labyrinth disorders     
Deafness unilateral  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Vertigo  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Eye disorders     
Diplopia  1  2/500 (0.40%)  3 0/500 (0.00%)  0
Macular oedema  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Retinal degeneration  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Retinopathy hypertensive  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Scleral oedema  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Vision blurred  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Gastrointestinal disorders     
Abdominal discomfort  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Abdominal pain  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Constipation  1  25/500 (5.00%)  25 25/500 (5.00%)  25
Diarrhoea  1  2/500 (0.40%)  2 6/500 (1.20%)  6
Dyspepsia  1  1/500 (0.20%)  2 0/500 (0.00%)  0
Dysphagia  1  6/500 (1.20%)  6 7/500 (1.40%)  7
Flatulence  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Haematemesis  1  1/500 (0.20%)  1 2/500 (0.40%)  2
Ileus  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Ileus paralytic  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Nausea  1  7/500 (1.40%)  7 8/500 (1.60%)  8
Stress ulcer  1  3/500 (0.60%)  3 3/500 (0.60%)  3
Tongue oedema  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Upper gastrointestinal haemorrhage  1 [1]  4/500 (0.80%)  4 1/500 (0.20%)  1
Vomiting  1  11/500 (2.20%)  11 13/500 (2.60%)  13
General disorders     
Administration site reaction  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Catheter site pain  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Chills  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Fatigue  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Oedema peripheral  1  0/500 (0.00%)  0 3/500 (0.60%)  3
Pain  1  1/500 (0.20%)  1 4/500 (0.80%)  4
Pyrexia  1 [1]  39/500 (7.80%)  40 30/500 (6.00%)  32
Hepatobiliary disorders     
Cholecystitis  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Hepatic cirrhosis  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Hepatic cyst  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Hepatic function abnormal  1 [1]  3/500 (0.60%)  4 3/500 (0.60%)  3
Hepatic steatosis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Hyperbilirubinaemia  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Liver disorder  1  1/500 (0.20%)  1 4/500 (0.80%)  4
Immune system disorders     
Hypersensitivity  1  1/500 (0.20%)  1 3/500 (0.60%)  3
Infections and infestations     
Bacteraemia  1  1/500 (0.20%)  1 2/500 (0.40%)  2
Bronchopneumonia  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Cellulitis  1  5/500 (1.00%)  5 6/500 (1.20%)  6
Clostridial infection  1 [1]  3/500 (0.60%)  3 0/500 (0.00%)  0
Clostridium difficile colitis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Dacryocystitis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Enterocolitis viral  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Erysipelas  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Infection  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Lung infection  1 [1]  12/500 (2.40%)  14 14/500 (2.80%)  14
Meningitis  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  2
Oral candidiasis  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Pharyngitis  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Pneumonia  1 [1]  11/500 (2.20%)  12 18/500 (3.60%)  20
Pneumonia pneumococcal  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Pyelonephritis chronic  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Respiratory tract infection  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Sinusitis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Staphylococcal infection  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Tonsillitis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Tracheobronchitis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Upper respiratory tract infection  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Urinary tract infection  1 [1]  24/500 (4.80%)  24 20/500 (4.00%)  20
Urinary tract infection fungal  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Injury, poisoning and procedural complications     
Abscess limb  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Contusion  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Excoriation  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Fall  1 [1]  6/500 (1.20%)  6 5/500 (1.00%)  5
Laceration  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Post transfusion purpura  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Investigations     
Activated partial thromboplastin time prolonged  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Blood albumin decreased  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Blood bilirubin increased  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Blood calcium decreased  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Blood chloride abnormal  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Blood chloride increased  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Blood cholesterol increased  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Blood lactate dehydrogenase increased  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Blood phosphorus decreased  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Blood potassium decreased  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Blood sodium increased  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Blood urine present  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Body temperature increased  1  1/500 (0.20%)  1 0/500 (0.00%)  0
C-reactive protein increased  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Coma scale abnormal  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Gastric occult blood positive  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Glycosylated haemoglobin increased  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Haematocrit decreased  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Haemoglobin decreased  1  1/500 (0.20%)  1 2/500 (0.40%)  2
Hepatic enzyme increased  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Laboratory test abnormal  1  2/500 (0.40%)  2 1/500 (0.20%)  1
Liver function test abnormal  1 [1]  2/500 (0.40%)  3 2/500 (0.40%)  2
Monocyte count increased  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Neutrophil count increased  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Occult blood positive  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Oxygen saturation decreased  1 [1]  0/500 (0.00%)  0 2/500 (0.40%)  2
PO2 decreased  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Platelet count decreased  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Procalcitonin increased  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Sputum culture positive  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Sputum increased  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Streptococcus test positive  1  1/500 (0.20%)  1 0/500 (0.00%)  0
White blood cell count increased  1  3/500 (0.60%)  3 4/500 (0.80%)  4
Metabolism and nutrition disorders     
Alkalosis  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Dyslipidaemia  1  0/500 (0.00%)  0 3/500 (0.60%)  3
Electrolyte imbalance  1  5/500 (1.00%)  5 7/500 (1.40%)  7
Gout  1  3/500 (0.60%)  3 1/500 (0.20%)  1
Hyperchloraemia  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Hyperglycaemia  1  3/500 (0.60%)  3 7/500 (1.40%)  7
Hyperhomocysteinaemia  1  4/500 (0.80%)  4 5/500 (1.00%)  5
Hyperkalaemia  1 [1]  5/500 (1.00%)  5 2/500 (0.40%)  2
Hyperlipidaemia  1  6/500 (1.20%)  6 4/500 (0.80%)  4
Hypermagnesaemia  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Hypernatraemia  1  11/500 (2.20%)  11 10/500 (2.00%)  10
Hyperphosphataemia  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Hypoalbuminaemia  1  0/500 (0.00%)  0 5/500 (1.00%)  5
Hypocalcaemia  1  10/500 (2.00%)  10 7/500 (1.40%)  7
Hypoglycaemia  1  1/500 (0.20%)  1 2/500 (0.40%)  2
Hypokalaemia  1  28/500 (5.60%)  32 38/500 (7.60%)  39
Hypomagnesaemia  1  2/500 (0.40%)  2 4/500 (0.80%)  4
Hyponatraemia  1 [1]  15/500 (3.00%)  16 6/500 (1.20%)  6
Hypophosphataemia  1  8/500 (1.60%)  8 9/500 (1.80%)  9
Hypoproteinaemia  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Metabolic acidosis  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Vitamin B12 deficiency  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Arthritis  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Back pain  1 [1]  2/500 (0.40%)  2 3/500 (0.60%)  3
Muscle spasms  1  3/500 (0.60%)  3 0/500 (0.00%)  0
Muscular weakness  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Musculoskeletal pain  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Pain in extremity  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Polyarthritis  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Rheumatoid arthritis  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Nervous system disorders     
Altered state of consciousness  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Amnesia  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Brain oedema  1 [1]  1/500 (0.20%)  1 5/500 (1.00%)  5
Brain stem infarction  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Cerebral haematoma  1 [1]  1/500 (0.20%)  1 1/500 (0.20%)  1
Cerebral haemorrhage  1 [1]  1/500 (0.20%)  1 2/500 (0.40%)  2
Cerebral infarction  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Cerebrovascular accident  1 [1]  4/500 (0.80%)  5 4/500 (0.80%)  5
Cognitive disorder  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Coma  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Consciousness fluctuating  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Convulsion  1 [1]  7/500 (1.40%)  7 4/500 (0.80%)  4
Depressed level of consciousness  1 [1]  1/500 (0.20%)  1 1/500 (0.20%)  1
Dizziness  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Encephalopathy  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Epilepsy  1 [1]  1/500 (0.20%)  1 1/500 (0.20%)  1
Haemorrhage intracranial  1 [1]  3/500 (0.60%)  3 8/500 (1.60%)  9
Headache  1  22/500 (4.40%)  25 17/500 (3.40%)  18
Hydrocephalus  1 [1]  4/500 (0.80%)  4 5/500 (1.00%)  5
Hypoaesthesia  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
IIIrd nerve paralysis  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Intracranial aneurysm  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Intracranial haematoma  1  3/500 (0.60%)  3 3/500 (0.60%)  3
Intracranial pressure increased  1 [1]  2/500 (0.40%)  2 0/500 (0.00%)  0
Intraventricular haemorrhage  1  1/500 (0.20%)  1 3/500 (0.60%)  3
Lethargy  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Loss of consciousness  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Mental impairment  1 [1]  1/500 (0.20%)  1 2/500 (0.40%)  2
Mental status changes  1 [1]  4/500 (0.80%)  4 2/500 (0.40%)  2
Neurological decompensation  1 [1]  3/500 (0.60%)  3 8/500 (1.60%)  8
Neurological symptom  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Partial seizures  1 [1]  3/500 (0.60%)  4 0/500 (0.00%)  0
Pneumocephalus  1  1/500 (0.20%)  2 0/500 (0.00%)  0
Presyncope  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Seizure like phenomena  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Somnolence  1 [1]  2/500 (0.40%)  2 0/500 (0.00%)  0
Speech disorder  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Subarachnoid haemorrhage  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Syncope  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Tremor  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Vasogenic cerebral oedema  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Psychiatric disorders     
Agitation  1  6/500 (1.20%)  7 13/500 (2.60%)  14
Anxiety  1  0/500 (0.00%)  0 3/500 (0.60%)  3
Confusional state  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Delirium  1  7/500 (1.40%)  7 8/500 (1.60%)  8
Delirium tremens  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Depressed mood  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Depression  1 [1]  0/500 (0.00%)  0 3/500 (0.60%)  3
Hallucination  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Insomnia  1  2/500 (0.40%)  2 1/500 (0.20%)  1
Psychotic disorder  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Restlessness  1  2/500 (0.40%)  2 2/500 (0.40%)  2
Sleep disorder  1  2/500 (0.40%)  2 4/500 (0.80%)  4
Renal and urinary disorders     
Blood creatinine abnormal  1 [6]  1/500 (0.20%)  1 0/500 (0.00%)  0
Blood creatinine decreased  1 [6]  0/500 (0.00%)  0 1/500 (0.20%)  1
Blood creatinine increased  1 [7]  2/500 (0.40%)  2 6/500 (1.20%)  6
Blood urea decreased  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Blood urea increased  1  3/500 (0.60%)  3 2/500 (0.40%)  2
Dysuria  1  2/500 (0.40%)  2 3/500 (0.60%)  3
Fluid overload  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Glomerular filtration rate increased  1 [6]  0/500 (0.00%)  0 1/500 (0.20%)  1
Haematuria  1 [1]  0/500 (0.00%)  0 3/500 (0.60%)  3
Hydronephrosis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Hypervolaemia  1 [8]  0/500 (0.00%)  0 1/500 (0.20%)  1
Hypovolaemia  1 [8]  0/500 (0.00%)  0 1/500 (0.20%)  1
Incontinence  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Nephropathy  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Neurogenic bladder  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Oliguria  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Pollakiuria  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Renal cyst  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Renal failure  1 [1]  1/500 (0.20%)  1 2/500 (0.40%)  2
Renal failure acute  1 [1]  5/500 (1.00%)  5 13/500 (2.60%)  13
Renal function test abnormal  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Renal impairment  1  3/500 (0.60%)  3 6/500 (1.20%)  6
Renal injury  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Urinary incontinence  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Urinary retention  1  4/500 (0.80%)  4 1/500 (0.20%)  1
Urine output decreased  1  0/500 (0.00%)  0 6/500 (1.20%)  6
Reproductive system and breast disorders     
Benign prostatic hyperplasia  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Breast mass  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Dysmenorrhoea  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Ovarian cyst  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Acute respiratory failure  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Aspiration  1 [1]  0/500 (0.00%)  0 2/500 (0.40%)  2
Atelectasis  1  2/500 (0.40%)  2 3/500 (0.60%)  3
Cough  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Dyspnoea  1 [1]  0/500 (0.00%)  0 4/500 (0.80%)  4
Epistaxis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Hypercapnia  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Hypoxia  1 [1]  2/500 (0.40%)  2 1/500 (0.20%)  1
Nasal congestion  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Pleural effusion  1 [1]  0/500 (0.00%)  0 1/500 (0.20%)  1
Pneumonia aspiration  1 [1]  15/500 (3.00%)  15 21/500 (4.20%)  23
Pulmonary congestion  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Pulmonary oedema  1 [1]  1/500 (0.20%)  1 2/500 (0.40%)  2
Respiratory distress  1 [1]  2/500 (0.40%)  2 1/500 (0.20%)  1
Respiratory failure  1 [1]  3/500 (0.60%)  3 0/500 (0.00%)  0
Sleep apnoea syndrome  1  2/500 (0.40%)  2 2/500 (0.40%)  2
Tachypnoea  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Wheezing  1  1/500 (0.20%)  1 1/500 (0.20%)  1
Skin and subcutaneous tissue disorders     
Blister  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Decubitus ulcer  1  2/500 (0.40%)  2 4/500 (0.80%)  4
Dermatitis contact  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Drug eruption  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Dry skin  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Eczema  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Erythema  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Generalised erythema  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Haemorrhage subcutaneous  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Pruritus  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Rash macular  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Skin disorder  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Skin fissures  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Urticaria  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Surgical and medical procedures     
Craniotomy  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Endotracheal intubation  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Gastrostomy tube insertion  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Stereotactic surgery  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Vascular disorders     
Arteriosclerosis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Arteriovenous fistula  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Axillary vein thrombosis  1  1/500 (0.20%)  1 0/500 (0.00%)  0
Deep vein thrombosis  1 [1]  5/500 (1.00%)  5 1/500 (0.20%)  1
Haematoma  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Haemorrhage  1 [1]  1/500 (0.20%)  1 0/500 (0.00%)  0
Phlebitis  1  18/500 (3.60%)  18 17/500 (3.40%)  17
Thrombophlebitis superficial  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Vena cava thrombosis  1  0/500 (0.00%)  0 1/500 (0.20%)  1
Venous thrombosis  1  2/500 (0.40%)  2 0/500 (0.00%)  0
Venous thrombosis limb  1  0/500 (0.00%)  0 2/500 (0.40%)  2
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (Unspecified)
[1]
(AE Not meeting SAE criteria)
[2]
Coded under vascular disorders, also analyzed with cardiac disorders for safety
[3]
Coded under investigations, also analyzed with cardiac disorders for safety
[4]
(AE Not meeting SAE criteria); coded under general disorders, also analyzed with cardiac disorders for safety
[5]
(AE Not meeting SAE criteria); coded under vascular disorders, also analyzed with cardiac disorders for safety
[6]
Coded under investigations, also analyzed with renal disorders for safety
[7]
(AE Not meeting SAE criteria) Coded under investigations, also analyzed with renal disorders for safety.
[8]
Coded under metabolism and nutrition disorders, also analyzed with renal disorders for safety
Treatment failures, randomization window, demographics, pre-randomization treatment, low death/disability, favorable baselines, and early termination could limit generalizability of primary (all with intent-to-treat) results and some sub-analyses.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The overall Principal Investigator IS, but the Data Coordination Unit (statistical) Principal Investigator IS NOT employed by the sponsor. Prior to release of a public-use data set, any study PIs/other collaborators may submit a proposal requesting data access, assistance with statistical analyses, and publication of additional results. All proposals are reviewed by a Publications Committee that includes the primary study PI, the statistical PI, the NINDS project scientist, and appointed others.
Results Point of Contact
Name/Title: Adnan I. Qureshi, MD
Organization: University of Minnesota
Phone: 612-624-2431
Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01176565     History of Changes
Other Study ID Numbers: 1207M17921
U01NS062091 ( U.S. NIH Grant/Contract )
U01NS061861 ( U.S. NIH Grant/Contract )
U01NS059041 ( U.S. NIH Grant/Contract )
U01NS056975 ( U.S. NIH Grant/Contract )
H23-4-3 ( Other Grant/Funding Number: Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center, Japan )
First Submitted: August 4, 2010
First Posted: August 6, 2010
Results First Submitted: January 1, 2017
Results First Posted: April 25, 2017
Last Update Posted: April 25, 2017