Clevidipine Bolus Administration in the Treatment of Hypertensive Patients Undergoing Cardiac Surgery (SPRINT)

Phase 2

Completed

• Conditions: Hypertension
• Interventions: Drug: clevidipine

• Registration Number: NCT00799604
• Lead Sponsor: The Medicines Company

Brief Summary

This study was designed to evaluate the pharmacodynamics of a bolus dosing regimen of clevidipine, a vascular-selective L-type calcium channel antagonist, for the management of blood pressure in cardiac surgery patients, as well as to evaluate the efficacy, safety and pharmacokinetics of clevidipine after bolus administration.

Detailed Description

Study participants were screened up to 14 days prior to their elective cardiac surgery. For the purpose of this study, hypertension was defined as systolic blood pressure (SBP) ≥140 mm Hg immediately prior to initiation of study drug.

On the day of surgery, an IV bolus dose of clevidipine (Bolus 1 - pre-anesthesia) was administered to each eligible study participant during Treatment Period 1 to decrease BP before induction of general anesthesia. The dose (either 125 μg, 250 μg or 500 μg) given was based on the assigned cohort for each participant, listed in the 'Arms' section below.

At the discretion of the investigator, a second IV bolus dose of clevidipine (Bolus 2 - with anesthesia) could have been administered during Treatment Period 2 at either 125 μg, 250 μg or 500 μg, based upon the earlier observed response to Bolus 1. This dose was administered after the induction of anesthesia, to decrease BP prior to cannulation of the ascending aorta for initiation of cardiopulmonary bypass.

Assessment of safety was performed throughout Treatment Periods 1 and 2 with Adverse Events (AEs) followed 6 hours post final bolus dose and Serious Adverse Events (SAEs) followed 24 hours post final bolus dose.

Study Timeline

• Study Start: 2008-11
• Study First Submitted: 2008-11-26
• Study First Submitted QC: 2008-11-28
• Study First Posted: 2008-12-01
• Primary Completion: 2009-10
• Study Completion: 2009-10
• Results First Submitted: 2012-07-30
• Results First Submitted QC: 2014-05-12
• Results First Posted: 2014-06-04
• Status Verified: 2014-08
• Last Update Submitted: 2014-08-21
• Last Update Posted: 2014-08-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Require elective cardiac operation involving the use of cardiopulmonary bypass
• Age 18 years or older
• A history or hypertension and/or expected to require perioperative antihypertensive therapy in the opinion of the investigator
• Written informed consent
• Pre-anesthesia baseline SBP ≥140 mm Hg just prior to bolus, measured using an arterial line

Exclusion Criteria

• Receiving either intravenous vasopressor or intravenous vasodilatory therapy in the 72 hours prior to dosing
• Critical left main coronary artery stenosis
• Critical aortic valve (<0.5 cm3) or mitral valve (<1.0 cm3) stenosis
• Acute myocardial infarction within the prior 14 days
• Fully paced cardiac rhythm
• Known or suspected aortic dissection
• Requiring preoperative intra-aortic balloon pump counterpulsation therapy
• Contraindication to transesophageal echocardiography
• Positive pregnancy test or breast feeding
• Intolerance or allergy to calcium channel blockers
• Allergy to soybean oil or egg lecithin
• Any condition(s) that in the Investigator's opinion would warrant exclusion from the study or prevent the patient from completing the study
• Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of enrollment

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
clevidipine	clevidipine	Patients were sequentially assigned to one of following three planned dose cohorts for Bolus 1 within the clevidipine arm: * Cohort 1: clevidipine 250 µg (0.5 mL) * Cohort 2: clevidipine 500 µg (1 mL) * Cohort 3: clevidipine 125 µg (0.25 mL or 0.5 mL of a 1:1 solution)

Primary Outcome Measures

Name	Time	Method
The Mean Maximum Absolute Change in Systolic Blood Pressure From Baseline Within 15 Minutes From the First Bolus Dose of Clevidipine (Treatment Period 1, Bolus 1 - Pre-anesthesia).	From start to 15 minutes of Bolus 1 dose of clevidipine (pre-anesthesia).	Blood Pressure was measured at 60, 45, 30, 0 seconds prior to first Bolus dose (Bolus 1), and every 5 seconds after Bolus 1 for 15 minutes. Baseline SBP of Bolus 1 is defined as, 'median of all measurements prior to or at the start of Bolus 1'. Locally weighted scatterplot smoothing (LOWESS) method was used to determine the minimum SBP value for each patient. Maximum absolute change is the minimum SBP value within 15 minutes from bolus 1 minus baseline value.
The Mean Maximum Percent Change in Systolic Blood Pressure From Baseline Within 15 Minutes From the First Bolus Dose of Clevidipine (Treatment Period 1, Bolus 1 - Pre-anesthesia).	From start to 15 minutes of Bolus 1 dose of clevidipine (pre-anesthesia).	Blood Pressure was measured at 60, 45, 30, 0 seconds prior to first Bolus dose (Bolus 1), and every 5 seconds after Bolus 1 for 15 minutes. Baseline SBP of Bolus 1 is defined as, 'median of all measurements prior to or at the start of Bolus 1'. Locally weighted scatterplot smoothing (LOWESS) method was used to determine the minimum SBP value for each patient. Maximum percent change is defined as the maximum absolute change divided by the baseline value of bolus 1 and multiplied by 100.

Secondary Outcome Measures

Name	Time	Method
The Percentage of Patients With Systolic Blood Pressure ≤85 mm Hg Within 15 Minutes From the First Bolus Dose of Clevidipine (Treatment Period 1, Bolus 1 - Pre-anesthesia).	From start to 15 minutes of Bolus 1 dose of clevidipine (pre-anesthesia).	The percentage is calculated using the number of patients with a systolic blood pressure ≤85 mm Hg within 15 minutes from the initial Bolus 1 dose divided by the total number of patients who were treated with a Bolus 1 clevidipine, and multiplied by 100.
The Median Time to 5%, 10%, and 15% Systolic Blood Pressure Reduction From Baseline Within 15 Minutes From the First Bolus Dose of Clevidipine (Treatment Period 1, Bolus 1 -Pre-anesthesia).	From start to 15 minutes of Bolus 1 of clevidipine (pre-anesthesia).	BP was measured at 60, 45, 30, 0 seconds prior to first Bolus dose (bolus 1), and every 5 seconds after Bolus 1 for 15 minutes. Baseline SBP of bolus 1 is defined as median of all measurements prior to or at the start of Bolus 1. The time at which first target SBP reduction (ex. 5%) from baseline was reached was identified for each patient using fitted values from LOWESS method. Kaplan-Meier method was used to estimate the median time. Patients who never reached 5%, 10% or 15% reduction, withdrew from study or changed antihypertensive within 15 minutes were censored.
The Mean Percent Change in Systolic Blood Pressure From Baseline Over Time During the First 15 Minutes Following First Bolus Dose of Clevidipine (Treatment Period 1, Bolus 1 - Pre-anesthesia).	From start to 15 minutes of Bolus 1 of clevidipine (pre-anesthesia).	BP was measured at 60, 45, 30, 0 seconds prior to first Bolus dose (Bolus 1), and every 5 seconds after Bolus 1 for 15 minutes. Baseline SBP of Bolus 1 is defined as median of all measurements prior to or at the start of Bolus 1. SBP change (percent change) from baseline is calculated at each collection time point after bolus 1 dose for each patient.
The Median Time to 50%, and, When Available, 90% Recovery From Maximum SBP Effect Following the First Bolus Dose of Clevidipine for Patients Who Achieved the Endpoints (Treatment Period 1, Bolus 1 - Pre-anesthesia).	Up to 15 minutes following the first bolus dose of clevidipine (pre-anesthesia).	Analysis is of the time in minutes between the recorded time at the maximum absolute change and the time of the systolic blood pressure value at the first 50% recovery. The 50% recovery value is equal to the minimum recorded systolic blood pressure value plus 50% of the maximum amount of systolic blood pressure reduction (the Bolus 1 baseline value minus the value at the maximum absolute change).
Change in Heart Rate After Bolus 1 (Pre-anesthesia).	Baseline up until the first 15 minutes following Bolus 1 (pre-anesthesia).	The baseline heart rate was measured as the median of all the heart rate measurements within 60 seconds or at the start of the administration of Bolus 1.

Trial Locations

Locations (2)

Massachusetts General Hospital, Harvard Medical School; 🇺🇸 Boston, Massachusetts, United States

Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States