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

An Open-label Study in Patients Undergoing Cardiac Surgery to Evaluate the Effect of Bolus Clevidipine Administration (SPRINT)

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.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: clevidipine

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 Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital, Harvard Medical School
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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)	Drug: clevidipine; Clevidipine (0.5mg/mL in 20% lipid emulsion) was administered as an IV bolus (<5 sec) by rapid injection for Bolus 1 and for Bolus 2, if second bolus dose was administered, directly into a peripheral venous catheter followed by a normal saline flush (10mL).; Other Names: clevidipine injectable emulsion; clevidipine emulsion; Cleviprex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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.	From start to 15 minutes of Bolus 1 dose of clevidipine (pre-anesthesia).
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).	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.	From start to 15 minutes of Bolus 1 dose of clevidipine (pre-anesthesia).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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.	From start to 15 minutes of Bolus 1 dose of clevidipine (pre-anesthesia).
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).	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.	From start to 15 minutes of Bolus 1 of clevidipine (pre-anesthesia).
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).	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.	From start to 15 minutes of Bolus 1 of clevidipine (pre-anesthesia).
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).	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).	Up to 15 minutes following the first bolus dose of clevidipine (pre-anesthesia).
Change in Heart Rate After 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.	Baseline up until the first 15 minutes following Bolus 1 (pre-anesthesia).

Collaborators and Investigators

• Sponsor: The Medicines Company
• Investigators: Principal Investigator: Albert T. Cheung, MD, University of Pennsylvania; Principal Investigator: Edwin G. Avery, IV, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: November 26, 2008
• First Submitted That Met QC Criteria: November 28, 2008
• First Posted (Estimate): December 1, 2008

Study Record Updates

• Last Update Posted (Estimate): August 29, 2014
• Last Update Submitted That Met QC Criteria: August 21, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Hypertension; Calcium Channel Blocker; Antihypertensive Agent
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Clevidipine
• Other Study ID Numbers: TMC-CLV-08-02