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

• The mean maximum absolute and percent change in systolic blood pressure from baseline within 15 minutes from the first bolus dose of clevidipine (pre-anesthesia). [ Time Frame: Within 15 minutes from the first bolus dose of clevidipine (pre-anesthesia). ] [ Designated as safety issue: No ]
  

• The percentage of patients with systolic blood pressure ≤85 mm Hg within 15 minutes from the first bolus dose of clevidipine (pre-anesthesia). [ Time Frame: Within 15 minutes from the first bolus dose of clevidipine (pre-anesthesia). ] [ Designated as safety issue: No ]
  
• The median time to 5%, 10%, and 15% systolic blood pressure reduction from baseline within 15 minutes from the first bolus dose of clevidipine (pre-anesthesia). [ Time Frame: Within 15 minutes from the first bolus dose of clevidipine (pre-anesthesia). ] [ Designated as safety issue: No ]
  
• The mean percent change in systolic blood pressure from baseline over time during the first 15 minutes following first bolus dose of clevidipine (pre-anesthesia). [ Time Frame: The first 15 minutes following first bolus dose of clevidipine (pre-anesthesia). ] [ Designated as safety issue: No ]
  
• The median time to 50% and, when available, 90% recovery from maximum systolic blood pressure effect following the first bolus dose of clevidipine (pre-anesthesia). [ Time Frame: Following the first bolus dose of clevidipine (pre-anesthesia). ] [ Designated as safety issue: No ]
  
• The area under the concentration versus time curve, maximum concentration, elimination half-life, clearance, volume of distribution, and elimination rate constant will be determined, if feasible, for each individual patient. [ Time Frame: Following the first bolus dose of clevidipine ] [ Designated as safety issue: No ]
  
• The following pharmacodynamic parameters will be determined, if feasible, for each individual patient following the first bolus dose of clevidipine: area under the effect-time curve, maximum effect, and time to maximum observed effect. [ Time Frame: Following the first bolus dose of clevidipine. ] [ Designated as safety issue: No ]
  
• The relationship between change in systolic blood pressure from baseline and the blood concentration of clevidipine following the first bolus dose. [ Time Frame: Following first bolus dose of clevidipine. ] [ Designated as safety issue: No ]
  
• Incidence of adverse events and serious adverse events. [ Time Frame: Adverse events will be followed for 6 hours and serious adverse events for up to 24 hours after the final bolus dose. ] [ Designated as safety issue: Yes ]
  
• Change in heart rate. [ Time Frame: Following the first bolus dose of clevidipine. ] [ Designated as safety issue: Yes ]
  

Drug: Clevidipine butyrate injectable emulsion
Clevidipine (0.5mg/mL in 20% lipid emulsion) in 100mL bottles will be administered as an IV bolus (<5 sec) by rapid injection, directly into a peripheral venous catheter followed by a normal saline flush (10mL). 10 patients will be allocated to each of the following 3 planned dose cohorts: 250μg (0.5mL), 500μg (1mL), 125μg (0.25mL or 0.5mL of a 1:1 solution). Patients will be given a bolus dose of clevidipine prior to anesthesia; at the discretion of the investigator, a second bolus may be administered after induction of anesthesia and immediately prior to aortic cannulation at either 125μg, 250μg or 500μg based on earlier observed response to Bolus 1. An additional dose cohort of up to 10 patients may be added if required at a dose between 125μg and 500μg; final determination of dose will be based on the results of Cohorts 1-3. In Cohort 4, if required, the final determination of the dose to be used for Bolus 2 will be based on the results of Bolus 1 and Cohorts 1-3.
Other Name: Cleviprex

This open-label, single-arm study is designed to demonstrate the efficacy and safety of a bolus dose of clevidipine, a vascular-selective L-type calcium channel antagonist, in the management of hypertension in patients undergoing cardiac surgery requiring the use of cardiopulmonary bypass.

Informed consent will be obtained from patients meeting the inclusion criteria before the initiation of any study-specific procedures. Prior to administration of study drug, a clinical examination will be carried out. For the purposes of this study, hypertension will be defined as systolic blood pressure ≥140 mm Hg immediately prior to initiation of study drug.

The study will occur in four separate periods: Screening period (-14 to -1 days), Treatment Period 1 (Day 1; before anesthesia to at least 15 minutes and up to 30 minutes after Bolus 1), Treatment Period 2 (Day 1; from the end of Treatment Period 1, after initiation of anesthesia to final bolus) and a Follow-up Period (up to 24 hours after final bolus), representing a maximum of 16 days on study.

It is planned that 10 patients will be allocated to each of the following 3 planned dose cohorts:

• 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)

If the initial 5 patients dosed in a cohort demonstrate no response in SBP (≤5-10 mm Hg change in SBP) patients will be enrolled into the next higher dose cohort. If ≥1 of the initial patients in a cohort demonstrates a response in SBP, the full 10 patients will be enrolled. When at least 5 patients are enrolled in a cohort, dose escalation will be terminated if ≥60% of patients, demonstrate a SBP of ≤85 mm Hg (pre-anesthesia).

Clevidipine will be administered prior to induction of general anesthesia in Treatment Period 1 as an intravenous bolus (<5 seconds) by rapid injection directly into a peripheral venous catheter followed by a normal saline flush (10 mL). At the discretion of the Investigator, a second bolus dose of clevidipine (Bolus 2) may be administered in Treatment Period 2, after induction of general anesthesia at either 125 μg, 250 μg or 500 μg based upon the earlier observed response to Bolus 1.

An additional dose cohort of up to 10 patients may be added if required (Cohort 4) in which clevidipine will be administered at a dose between 125 μg and 500 μg. The final determination of the dose to be used in Cohort 4 will be based on the results of Cohorts 1, 2 and 3.

Assessment of safety will be performed throughout the treatment period and for at least 6 hours after termination of study drug. Patients will be followed for up to 24 hours after the final bolus dose.