Trial Outcomes & Findings for Antihypertensive Treatment of Acute Cerebral Hemorrhage-II (NCT NCT01176565)

Last Updated: 2017-04-25

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

1000 participants

Primary outcome timeframe

90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization

Results posted on

2017-04-25

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Standard SBP Reduction Arm 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.	Intensive SBP Reduction Arm 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 Study STARTED	500	500
Overall Study COMPLETED	480	481
Overall Study NOT COMPLETED	20	19

Reasons for withdrawal

Reasons for withdrawal
Measure	Standard SBP Reduction Arm 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.	Intensive SBP Reduction Arm 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 Study Lost to Follow-up	12	16
Overall Study Withdrawal by Subject	7	1
Overall Study Not Analyzed (any other reason)	1	2

Baseline Characteristics

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.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Standard SBP Reduction Arm n=500 Participants 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.	Intensive SBP Reduction Arm n=500 Participants 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 n=1000 Participants Total of all reporting groups
Age, Continuous	61.9 years STANDARD_DEVIATION 13.1 • n=500 Participants	62 years STANDARD_DEVIATION 13.1 • n=500 Participants	61.93 years STANDARD_DEVIATION 13.1 • n=1000 Participants
Sex: Female, Male Female	184 Participants n=500 Participants	196 Participants n=500 Participants	380 Participants n=1000 Participants
Sex: Female, Male Male	316 Participants n=500 Participants	304 Participants n=500 Participants	620 Participants n=1000 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	41 Participants n=500 Participants	38 Participants n=500 Participants	79 Participants n=1000 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	446 Participants n=500 Participants	446 Participants n=500 Participants	892 Participants n=1000 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	13 Participants n=500 Participants	16 Participants n=500 Participants	29 Participants n=1000 Participants
Race/Ethnicity, Customized Race · Asian	285 Participants n=500 Participants	277 Participants n=500 Participants	562 Participants n=1000 Participants
Race/Ethnicity, Customized Race · Black	58 Participants n=500 Participants	73 Participants n=500 Participants	131 Participants n=1000 Participants
Race/Ethnicity, Customized Race · White	145 Participants n=500 Participants	142 Participants n=500 Participants	287 Participants n=1000 Participants
Race/Ethnicity, Customized Race · Other or unknown	12 Participants n=500 Participants	8 Participants n=500 Participants	20 Participants n=1000 Participants
Recruited at site in Asia	273 Participants n=500 Participants	264 Participants n=500 Participants	537 Participants n=1000 Participants
First Glasgow Coma Scale Score assessed upon hospital emergency department (ED) arrival ED arrival GCS score = 3 - 11	74 Participants n=500 Participants	73 Participants n=500 Participants	147 Participants n=1000 Participants
First Glasgow Coma Scale Score assessed upon hospital emergency department (ED) arrival ED arrival GCS score = 12 - 14	142 Participants n=500 Participants	152 Participants n=500 Participants	294 Participants n=1000 Participants
First Glasgow Coma Scale Score assessed upon hospital emergency department (ED) arrival ED arrival GCS score = 15	284 Participants n=500 Participants	275 Participants n=500 Participants	559 Participants n=1000 Participants
Systolic Blood Pressure at presentation in hospital emergency department (ED)	201.1 mmHg STANDARD_DEVIATION 26.9 • n=499 Participants • 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.	200 mmHg STANDARD_DEVIATION 27.1 • n=500 Participants • 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.	200.6 mmHg STANDARD_DEVIATION 27.0 • n=999 Participants • 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)	11 units on a scale (NIHSS range 0 - 42) n=500 Participants	11 units on a scale (NIHSS range 0 - 42) n=500 Participants	11 units on a scale (NIHSS range 0 - 42) n=1000 Participants
Intracerebral Hematoma Volume	10.2 cubic centimeters (cm3) n=492 Participants • 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.	10.3 cubic centimeters (cm3) n=496 Participants • 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.	10.3 cubic centimeters (cm3) n=988 Participants • 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	51 Participants n=492 Participants • 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.	45 Participants n=496 Participants • 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.	96 Participants n=988 Participants • 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	142 Participants n=492 Participants • 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.	122 Participants n=496 Participants • 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.	264 Participants n=988 Participants • 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 Thalamus	180 Participants n=492 Participants • 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.	193 Participants n=496 Participants • 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.	373 Participants n=988 Participants • 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.
Location of Hemorrhage Basal ganglia	251 Participants n=492 Participants • 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.	255 Participants n=496 Participants • 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.	506 Participants n=988 Participants • 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.
Location of Hemorrhage Cerebral lobe	60 Participants n=492 Participants • 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.	48 Participants n=496 Participants • 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.	108 Participants n=988 Participants • 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.
Location of Hemorrhage Cerebellum	1 Participants n=492 Participants • 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.	0 Participants n=496 Participants • 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.	1 Participants n=988 Participants • 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	84 Participants n=500 Participants	80 Participants n=500 Participants	164 Participants n=1000 Participants
Other prior nervous system disorders	17 Participants n=500 Participants	23 Participants n=500 Participants	40 Participants n=1000 Participants
History of congestive heart failure	21 Participants n=500 Participants	16 Participants n=500 Participants	37 Participants n=1000 Participants
History of atrial fibrillation	16 Participants n=500 Participants	20 Participants n=500 Participants	36 Participants n=1000 Participants
Myocardial infarction in the previous 3 months	0 Participants n=500 Participants	1 Participants n=500 Participants	1 Participants n=1000 Participants
History of coronary artery disease	17 Participants n=500 Participants	27 Participants n=500 Participants	44 Participants n=1000 Participants
History of hypertension	382 Participants n=500 Participants	411 Participants n=500 Participants	793 Participants n=1000 Participants
History of peripheral vascular disease	13 Participants n=500 Participants	9 Participants n=500 Participants	22 Participants n=1000 Participants
History of hyperlipidemia	119 Participants n=500 Participants	122 Participants n=500 Participants	241 Participants n=1000 Participants
History of cardiac dysrhythmias	21 Participants n=500 Participants	17 Participants n=500 Participants	38 Participants n=1000 Participants
History of diabetes mellitus Type 2	83 Participants n=500 Participants	92 Participants n=500 Participants	175 Participants n=1000 Participants
Previous use of antihypertensive drugs	235 Participants n=500 Participants	260 Participants n=500 Participants	495 Participants n=1000 Participants
Symptom onset to randomization time, minutes	184.7 minutes STANDARD_DEVIATION 56.7 • n=500 Participants	182.2 minutes STANDARD_DEVIATION 57.2 • n=500 Participants	183.5 minutes STANDARD_DEVIATION 57 • n=1000 Participants
Symptom onset to nicardipine infusion time	165.3 minutes STANDARD_DEVIATION 101.3 • n=479 Participants • 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.	149 minutes STANDARD_DEVIATION 65 • n=497 Participants • 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.	157 minutes STANDARD_DEVIATION 85.2 • n=976 Participants • 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	141.1 mmHg STANDARD_DEVIATION 14.8 • n=497 Participants • 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.	128.9 mmHg STANDARD_DEVIATION 16 • n=500 Participants • 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.	135 mmHg STANDARD_DEVIATION 16.6 • n=997 Participants • 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	4 Participants n=500 Participants	61 Participants n=500 Participants	65 Participants n=1000 Participants
Failure to attain systolic blood pressure target for 2 consecutive hours during 2-24 hours	7 Participants n=500 Participants	78 Participants n=500 Participants	85 Participants n=1000 Participants

PRIMARY outcome

Timeframe: 90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization

Population: 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.

Outcome measures

Outcome measures
Measure	Standard SBP Reduction Arm n=500 Participants 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.	Intensive SBP Reduction Arm n=500 Participants 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.
Death or Disability According to Modified Rankin Scale Score at 90 Days (3 Months) From Randomization Death or disability at 90 days (mRS = 4 - 6)	181 Participants	186 Participants
Death or Disability According to Modified Rankin Scale Score at 90 Days (3 Months) From Randomization Known death at or before 90 days	34 Participants	33 Participants

SECONDARY outcome

Timeframe: 90 days (± 14 days per protocol window; up to ± 30 days data is used) from randomization

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Standard SBP Reduction Arm n=473 Participants 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.	Intensive SBP Reduction Arm n=472 Participants 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.
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 EQ-5D utility scale questionnaire	0.7 units on a scale Interval 0.0 to 1.0	0.7 units on a scale Interval -0.109 to 1.0
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 EQ VAS (visual analog scale)	70 units on a scale Interval 0.0 to 100.0	62.5 units on a scale Interval 0.0 to 100.0

SECONDARY outcome

Timeframe: From the baseline head CT to the 24 +/- 6 hours from randomization head CT

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Standard SBP Reduction Arm n=426 Participants 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.	Intensive SBP Reduction Arm n=450 Participants 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.
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.)	104 Participants	85 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From randomization through the 24-hour treatment period

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Standard SBP Reduction Arm n=500 Participants 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.	Intensive SBP Reduction Arm n=500 Participants 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.
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.	40 Participants	55 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From randomization through 72 hours from randomization

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Standard SBP Reduction Arm n=500 Participants 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.	Intensive SBP Reduction Arm n=500 Participants 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.
Hypotension Within 72 Hours	3 Participants	6 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From randomization through 72 hours (3 days)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Standard SBP Reduction Arm n=500 Participants 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.	Intensive SBP Reduction Arm n=500 Participants 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.
Treatment-related Serious Adverse Event Within 72 Hours of Randomization	6 Participants	8 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Standard SBP Reduction Arm n=500 Participants 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.	Intensive SBP Reduction Arm n=500 Participants 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.
Any Serious Adverse Event Within the 90-day Study Period	100 Participants	128 Participants

Adverse Events

Standard SBP Reduction Arm

Serious events: 100 serious events

Other events: 500 other events

Deaths: 0 deaths

Intensive SBP Reduction Arm

Serious events: 128 serious events

Other events: 500 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Adnan I. Qureshi, MD

University of Minnesota

Phone: 612-624-2431

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER