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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Hypertension, Hemorrhage

Intervention / Treatment
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* Drug: clevidipine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: clevidipine<br>This will be a single-arm study with no reference therapy. | Drug: clevidipine<br>* Clevidipine injectable emulsion (0.5 mg/mL) in 20% lipid emulsion in 100 mL bottles was administered intravenously to all patients via a single dedicated line. Clevidipine was 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 systolic blood pressure (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. The clevidipine infusion rate could be increased or decreased to maintain systolic blood pressure for up to a maximum of 96 hours.<br>* Other names: Cleviprex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Achieve Target SBP Range (≤160 mmHg to ≥140 mmHg) Within 30 Minutes of Initiation of Clevidipine | The median time, in minutes, was estimated with its two-tailed 95% confidence interval from the time of the initiation of clevidipine infusion until the first observed SBP was achieved in the target range of ≤160 mmHg to ≥140 mmHg within the first 30 minutes of clevidipine treatment. If patients did not reach the blood pressure target range within the first 30 minutes, their data was considered censored at 30 minutes. If another IV and/or oral antihypertensive agent indicated for hypertension was administered less than 30 minutes prior to achieving the endpoint, the data was considered censored at the time when the additional or alternative antihypertensive agent was given. | Within 30 minutes of study drug initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving a SBP of ≤160 mmHg Within 30 Minutes of Initiation of Clevidipine | The percentage of patients who reached SBP of ≤160 mmHg within the first 30 minutes of initiation of clevidipine infusion was summarized. If an additional or alternative IV antihypertensive agent and/or oral antihypertensive agent was administered for hypertension prior to a patient achieving SBP≤160 mmHg during the initial 30-minute treatment period, then the patient was considered to have failed to reach this efficacy endpoint. | Within 30 minutes of study drug initiation | 
| Percent Change From Baseline in Systolic Blood Pressure During the Initial 30 Minutes of Clevidipine Infusion | Over the initial 30 minutes of the treatment period, the percent change from baseline (defined as immediately prior to study drug initiation) was summarized descriptively at 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, 25, and 30 minutes after clevidipine initiation. Decreases in SBP from baseline were observed over the course of this time period. | Baseline through 30 minutes post initiation 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 | Total AUC-SBP captures the magnitude and duration of SBP either above the upper limit of the target SBP range at 160 mm Hg or below the lower limit of 140 mm Hg and normalized per hour for the duration of clevidipine infusion. A larger value for AUC-SBP indicates greater SBP variability outside the target range. | Duration of the study drug infusion (up to 96 hours) | 
| 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 | The percent time that SBP was maintained within the SBP target range (≤160 mmHg to ≥140 mmHg) was summarized for each 24-hour period of monotherapy of clevidipine infusion through 96 hours (0 -≤24 h, 24-≤48 h, 48-≤72 h, 72-≤96 h). For purposes of this analysis, SBP data were available from all mITT patients for the overall infusion period and from 0 to ≤24 hours of infusion; however, data was only available for 8 patients from 24 to ≤48 hours, 4 patients from 48 to ≤72 hours and 1 patient from 72 to ≤96 hours due to the variability in infusion durations >24 hours across patients. | From study drug initiation through termination (up to 96 h) | 
| Mean Dose of Clevidipine During the Treatment Period | Mean total dose of clevidipine from study drug initiation to the end of clevidipine treatment | Up to 96 hours | 
| Median Dose of Clevidipine During the Treatment Period | Mean total dose of clevidipine from study drug initiation to the end of clevidipine treatment | Up to 96 hours | 
| Proportion of Patients Requiring an Additional or Alternative Antihypertensive Agent(s) With or Without Clevidipine | Additional or alternative antihypertensive agent(s) comprise the use of other antihypertensive agent(s) either with clevidipine (additional) or in place of clevidipine (alternative) for the indication of hypertension from the time of clevidipine initiation to clevidipine termination. For purposes of this analysis, additional or alternative antihypertensive agents did not include oral antihypertensives that were administered in order to transition IV clevidipine-treated patients to oral therapy during the transition period of the study. | Up to 96 hours | 
| Percent Change in Heart Rate During 30 of Initiation of Clevidipine | Multiple timepoints were assessed (minutes 1, 2, 3, 4, 5, 10, 15, 20, 30) for analysis of percent change in heart rate during the initial 30 minutes. | From study drug initiation through each specified timepoint | 
| The Percentage of Patients Whose Systolic Blood Pressure is <90 mmHg Within 30 Minutes of the Initiation of Clevidipine Infusion |  | Within 30 minutes of the initiation of study drug infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Hemorrhage, Intracranial Pressure, Antihypertensive Agent, Calcium Channel Blocker