Clevidipine in the Treatment of Patients With Acute Hypertension and Intracerebral Hemorrhage (ACCELERATE)

Condition(s) targeted: Hypertension; Hemorrhage

Intervention: clevidipine (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: The Medicines Company

Official(s) and/or principal investigator(s):
Carmelo Graffagnino, MD, Principal Investigator, Affiliation: Duke University

The purpose of this study was to determine the efficacy and safety of clevidipine for treating acute hypertension (high blood pressure, defined as systolic blood pressure >160 mmHg) in patients with intracerebral hemorrhage (i. e., bleeding in the brain; stroke).

Official title: The Evaluation of Patients With Acute Hypertension and Intracerebral Hemorrhage With Intravenous Clevidipine Treatment (ACCELERATE)

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Median Time to Achieve Target SBP Range (≤160 mmHg to ≥140 mmHg) Within 30 Minutes of Initiation of Clevidipine

Secondary outcome:

Percentage of Participants Achieving a SBP of ≤160 mmHg Within 30 Minutes of Initiation of Clevidipine

Percent Change From Baseline in Systolic Blood Pressure During the Initial 30 Minutes of Clevidipine Infusion

Magnitude, Frequency and Duration of Systolic Blood Pressure Excursions (Calculated as Area Under the Curve [AUC]) Outside the Target Range Normalized Per Hour for the Duration of the Clevidipine Monotherapy Infusion

Percent Time Blood Pressures Were Maintained Within the Target Range (Systolic Blood Pressure ≤160 mmHg to ≥140 mmHg) Over Each 24 Hour Period During Monotherapy Infusion of Clevidipine

Mean Dose of Clevidipine During the Treatment Period

Median Dose of Clevidipine During the Treatment Period

Proportion of Patients Requiring an Additional or Alternative Antihypertensive Agent(s) With or Without Clevidipine

Percent Change in Heart Rate During 30 of Initiation of Clevidipine

The Percentage of Patients Whose Systolic Blood Pressure is <90 mmHg Within 30 Minutes of the Initiation of Clevidipine Infusion

Detailed description: This was a multicenter, single-arm, non-blinded dose titration efficacy and safety trial evaluating the ability of clevidipine, a vascular-selective L-type calcium channel antagonist, to rapidly control acute hypertension in patients with intracerebral hemorrhage. Informed consent was obtained from patients meeting the inclusion criteria before the initiation of any study-specific procedures. At screening, a clinical and neurological examination was carried out. For the purposes of this study, acute hypertension was defined as SBP >160 mmHg immediately prior to initiation of study drug. Approximately 30 to 40 patients with acute intracerebral hemorrhage (ICH) were planned to be enrolled with approximately 10 patients requiring monitoring of intracranial pressure (ICP). Infusion of study drug was initiated within 12 hours of ICH symptom onset. All eligible patients enrolled received clevidipine in an open label manner. Clevidipine was to be infused at an initial rate of 2. 0 mg/h for the first 1. 5 minutes. Thereafter, titration to higher infusion rates were to be attempted as needed, to obtain the target SBP range (SBP ≤160 mmHg to ≥140 mmHg). Titration to effect was to proceed by doubling the dose every 1. 5 minutes, up to a maximum of 32. 0 mg/h, until the desired effect (SBP within the target range) was attained. During the first 30 minutes, if the desired blood pressure lowering effect was not attained or maintained, an alternative intravenous (IV) antihypertensive agent(s), advised to be a different class other than calcium channel blockers, could be used with or without stopping the clevidipine infusion. The clevidipine infusion could continue for up to a maximum of 96 hours. Twenty-four hour follow-up computerized tomography (CT) scan results were recorded, including measurement of intracerebral hematoma volumes. Assessment of safety was performed throughout the treatment period and until 6 hours after termination of study drug. Patients were followed for 7 days following termination of the clevidipine infusion.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- CT evidence of intracerebral hemorrhage (diagnosis and treatment within 12 hours of

symptom onset)

- Age 18 years or older

- Baseline systolic blood pressure (immediately prior to initiation of clevidipine)

>160 mmHg measured using an arterial line. ICP-monitored patients enrolled in the sub-study were enrolled if SBP at the time of enrollment was ≤160 mmHg

- Required antihypertensive therapy to achieve systolic blood pressure ≤160 mmHg

- Written informed consent obtained

Exclusion Criteria:

- Decision for early surgical evacuation prior to 30 minutes of clevidipine

- Receipt of an oral antihypertensive within 2 hours prior to initiation of clevidipine

- Treatment with a continuous infusion of an IV antihypertension agent prior to

initiation of clevidipine. Bolus treatment with urapidil (Germany only), labetalol or hydralazine was permitted. ICP-monitored patients enrolled in the sub-study could be enrolled with a continuous infusion of an IV antihypertensive agent prior to the initiation of clevidipine.

- Intracerebral hematoma considered to be related to trauma by the neurologist or

neurosurgeon

- Aneurysmal sub-arachnoid hemorrhage

- Glasgow coma score of <5 and fixed dilated pupils

- Expectation that the patient would not tolerate or require intravenous

antihypertensive therapy for a minimum of 30 minutes

- Known or suspected aortic dissection

- Acute myocardial infarction on presentation

- Positive pregnancy test or known pregnancy

- Intolerance or allergy to calcium channel blockers

- Allergy to soybean oil or egg lecithin

- Known liver failure, cirrhosis or pancreatitis

- Prior directives against advanced life support

- Participation in other clinical research studies involving the evaluation of other

investigational drugs or devices within 30 days of enrollment

Universitatsklinikum Erlangen, Erlangen D91054, Germany

Universitatsklinikum Heidelberg, Heidelberg D69120, Germany

Washington Hospital Center, Washington, District of Columbia 20010-2975, United States

The Queens Medical Center, Honolulu, Hawaii 96813, United States

Universitätsklinikum Leipzig, Liebigstraße 22a, Leipzig D-04103, Germany

The John Hopkins Hospital, Baltimore, Maryland 21287, United States

Maine Medical Center, Portland, Massachusetts 04102, United States

Henry Ford Hospital, Detroit, Michigan 48202, United States

Columbia University Medical Center, New York, New York 10032, United States

Duke University Medical Center, Durham, North Carolina 27710, United States

Guilford Neurologic - Moses H Cone Health System, Greensboro, North Carolina 27405, United States

Cleveland Clinic Hospitals, Cleveland, Ohio 44195, United States

The Ohio State University, Columbus, Ohio 43210, United States

Thomas Jefferson University Stroke Research, Philadelphia, Pennsylvania 19107, United States

Medical University of South Carolina, Charleston, South Carolina 29425, United States

The University Health Science Center at S.A., San Antonio, Texas 78229-3900, United States

Intermountain Medical Center, Murray, Utah 84157, United States

Starting date: June 2008
Last updated: August 21, 2014