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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 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| clevidipine | Experimental | Patients were sequentially assigned to one of following three planned dose cohorts for Bolus 1 within the clevidipine arm:
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| clevidipine | Drug | 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). |
| 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). |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Albert T. Cheung, MD | University of Pennsylvania | Principal Investigator |
| Edwin G. Avery, IV, MD | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts General Hospital, Harvard Medical School | Boston | Massachusetts | 02114 | United States | ||
A screening period began up to 14 days prior to study drug administration, consisting of obtaining informed consent, confirming patient eligibility, and collecting screening assessments. Patient eligibility was further verified on treatment day to confirm SPB ≥140 mm Hg prior to study drug. If SBP was <140 mm Hg, no study drug was administered.
Thirty patients were enrolled at two hospitals. All received an initial dose of clevidipine (Bolus 1-pre-anesthesia) during Treatment Period 1; 21 participants received a second bolus dose (Bolus 2-with anesthesia)during Treatment 2 per the discretion of the investigator at 250, 500 or 125μg, depending on patient response to Bolus 1.
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| ID | Title | Description |
|---|---|---|
| FG000 | Planned Cohort 1: Clevidipine 250 μg (0.5 mL) | Clevidipine was administered at 250 μg during Treatment Period 1 prior to induction of general anesthesia as an IV bolus (<5 seconds) (Bolus 1 - pre-anesthesia) by rapid injection. At the discretion of the investigator, a second bolus (Bolus 2 - with anesthesia) could be administered during Treatment Period 2 after induction of general anesthesia at 125 μg, 250 μg or 500 μg based upon the earlier observed response to Bolus 1. Five participants who received a Bolus 1 dose of 250 μg during Treatment Period 1 and one participant who received a Bolus 1 dose of 125 μg during Treatment Period 1 received a Bolus 2 dose of 250 μg during Treatment Period 2 in this cohort. |
| FG001 | Planned Cohort 2: Clevidipine 500 μg (1.0 mL) | Clevidipine was administered at 500 μg during Treatment Period 1 prior to induction of general anesthesia as an IV bolus (<5 seconds) (Bolus 1 - pre-anesthesia) by rapid injection. At the discretion of the investigator, a second bolus (Bolus 2 - with anesthesia) could be administered during Treatment Period 2 after induction of general anesthesia at 125 μg, 250 μg or 500 μg based upon the earlier observed response to Bolus 1. Six participants who received a Bolus 1 dose of 500 μg and six participants who received a Bolus 1 dose of 125 μg during Treatment Period 1 received a Bolus 2 dose of 500 μg during Treatment Period 2 in this cohort. |
| FG002 | Planned Cohort 3: Clevidipine 125 μg (0.25 mL or 0.5mL Sol) | Clevidipine was administered at 125 μg during Treatment Period 1 prior to induction of general anesthesia as an IV bolus (<5 seconds) (Bolus 1 - pre-anesthesia) by rapid injection. At the discretion of the investigator, a second bolus (Bolus 2 - with anesthesia) could be administered during Treatment Period 2 after induction of general anesthesia at 125 μg, 250 μg or 500 μg based upon the earlier observed response to Bolus 1. Three participants who received a Bolus 1 dose of 250 μg during Treatment Period 1 received a Bolus 2 dose of 125 μg during Treatment Period 2 in this cohort. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bolus 1 (Pre-anesthesia) |
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| Bolus 2 (With Anesthesia) |
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These analyses include the Safety population defined as all participants, irrespective of eligibility, who were enrolled in Treatment Period 1 (Bolus 1 - pre-anesthesia) and were dosed with clevidipine. The number of participants in the Safety population and Modified Intent-To-Treat (mITT) population are identical.
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1: Clevidipine 250 μg (0.5 mL) | Baseline characteristics are reflective of the participant groupings during Treatment Period 1 (10 participants per cohort) during which clevidipine was administered at 250 μg prior to induction of general anesthesia as an IV bolus (Bolus 1 - pre-anesthesia) by rapid injection (<5 seconds). |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Modified Intent-to-Treat (mITT) population: all enrolled patients who were deemed eligible for the study by meeting all inclusion and no exclusion criteria and were treated with clevidipine. The mITT population is the primary population for the analyses of efficacy. | Posted | Mean | Standard Deviation | mm Hg | From start to 15 minutes of Bolus 1 dose of clevidipine (pre-anesthesia). |
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Non-serious AE(s) were documented and assessed following initiation of clevidipine administration through 6 hours post final bolus dose. SAEs were assessed up to 24 hours post final bolus dose, regardless of causal relationship to the study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | All Participants Across All Cohorts and Treatment Periods | Study participants were sequentially assigned one of three cohorts to receive either a 250 μg, 500 μg or 125 μg bolus dose of clevidipine during Treatment Period 1 prior to induction of general anesthesia (Bolus 1 - pre-anesthesia) by rapid injection (<5 seconds). At the discretion of the investigator, a second bolus could be administered during Treatment Period 2 after induction of general anesthesia (Bolus 2 - with anesthesia) at 125 μg, 250 μg or 500 μg based upon the earlier observed response to Bolus 1. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Encephalopathy | Nervous system disorders | MedDRA (11.0) | Systematic Assessment | unrelated |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acidosis | Metabolism and nutrition disorders | MedDRA (6.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jason Campagna. MD, PhD | The Medicines Company | 973-290-6199 | jason.campagna@themedco.com |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C118563 | clevidipine |
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| 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). |
| Hospital of the University of Pennsylvania |
| Philadelphia |
| Pennsylvania |
| 19104 |
| United States |
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| NOT COMPLETED |
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| Cohort 2: Clevidipine 500 μg (1.0 mL) |
Baseline characteristics are reflective of the participant groupings during Treatment Period 1 (10 participants per cohort) during which Clevidipine was administered at 250 μg prior to induction of general anesthesia as an IV bolus (Bolus 1 - pre-anesthesia) by rapid injection (<5 seconds). |
| BG002 | Cohort 3: Clevidipine 125 μg ( mL) | Baseline characteristics are reflective of the participant groupings during Treatment Period 1 (10 participants per cohort) during which clevidipine was administered at 250 μg prior to induction of general anesthesia as an IV bolus (Bolus 1 - pre-anesthesia) by rapid injection (<5 seconds). |
| BG003 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | These results represent Treatment Period 1 (Bolus 1 - pre-anesthesia). | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | These results represent participant groupings during Treatment Period 1 (Bolus 1 - pre-anesthesia). | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | These results represent patient groupings during Treatment Period 1 (Bolus 1 - pre-anesthesia). | Number | participants |
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| Height | These results represent the participant groupings during Treatment Period 1 (Bolus 1 - pre-anesthesia). | Mean | Standard Deviation | centimeters (cm) |
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| Weight | These results represent the participant groupings during Treatment Period 1 (Bolus 1 - pre-anesthesia). | Mean | Standard Deviation | kilograms (kg) |
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| Screening Blood Pressure | These results represent the participant groupings in Treatment Period 1 (Bolus 1 - pre-anesthesia). | Mean | Standard Deviation | mm Hg |
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| Screening Heart Rate | These results represent the participant groupings during Treatment Period 1 (Bolus 1 - pre-anesthesia). | Mean | Standard Deviation | Beats Per Minute (BPM) |
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| Cohort 1: Clevidipine 250 μg (0.5 mL) |
Clevidipine was administered at 250 μg during Treatment Period 1 prior to induction of general anesthesia as an IV bolus (Bolus 1 - pre-anesthesia) by rapid injection (<5 seconds). |
| OG001 | Cohort 2: Clevidipine 500 μg (1.0 mL) | Clevidipine was administered at 500 μg during Treatment Period 1 prior to induction of general anesthesia as an IV bolus (Bolus 1 - pre-anesthesia) by rapid injection (<5 seconds). |
| OG002 | Cohort 3: Clevidipine 125 μg (0.25 mL or 0.5 mL of a 1:1 Sol) | Clevidipine was administered at 125 μg during Treatment Period 1 prior to induction of general anesthesia as an IV bolus (Bolus 1 - pre-anesthesia) by rapid injection (<5 seconds). |
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| Secondary | 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. | Modified Intent-to-Treat (mITT) population: all enrolled patients who are eligible for the study and treated with clevidipine. The mITT population will be the primary population for the analyses of efficacy. | Posted | Number | 95% Confidence Interval | percent patients | From start to 15 minutes of Bolus 1 dose of clevidipine (pre-anesthesia). |
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| Secondary | 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. | Modified Intent-to-Treat (mITT) population: all enrolled patients who are eligible for the study and treated with clevidipine. The mITT population will be the primary population for the analyses of efficacy. | Posted | Median | 95% Confidence Interval | minutes | From start to 15 minutes of Bolus 1 of clevidipine (pre-anesthesia). |
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| Secondary | 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. | Modified Intent-to-Treat (mITT) population: all enrolled patients who are eligible for the study and treated with clevidipine. The mITT population will be the primary population for the analyses of efficacy. | Posted | Mean | Standard Deviation | percent change | From start to 15 minutes of Bolus 1 of clevidipine (pre-anesthesia). |
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| Secondary | 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). | Modified Intent-to-Treat (mITT) population: all enrolled patients who are eligible for the study and treated with clevidipine. The mITT population will be the primary population for the analyses of efficacy. | Posted | Median | 95% Confidence Interval | minutes | Up to 15 minutes following the first bolus dose of clevidipine (pre-anesthesia). |
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| Secondary | 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. | Safety population: all enrolled patients (irrespective of eligibility) who are dosed with clevidipine. The safety population will be the primary population used for the safety analyses. | Posted | Mean | Standard Deviation | beats per minute (bpm) | Baseline up until the first 15 minutes following Bolus 1 (pre-anesthesia). |
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| Primary | 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. | Modified Intent-to-Treat (mITT) population: all enrolled patients who were deemed eligible for the study by meeting all inclusion and no exclusion criteria and were treated with clevidipine. The mITT population is the primary population for the analyses of efficacy. | Posted | Mean | Standard Deviation | percent change | From start to 15 minutes of Bolus 1 dose of clevidipine (pre-anesthesia). |
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| 1 |
| 30 |
| 12 |
| 30 |
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| Atelectasis | Respiratory, thoracic and mediastinal disorders | MedDRA (6.1) | Systematic Assessment |
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| Hypotension | Vascular disorders | MedDRA (6.1) | Systematic Assessment |
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The site agrees that publication of Study results at the site is not permitted until after the presentation and publication of the multi-center results or an affirmative decision is made by Sponsor not to proceed with such publication. In such a case, Sponsor shall provide access to all Study site data to the academic Study Coordination Center, or upon request Sponsor will provide access to all Study site data to Institution. The site will adhere to terms for Sponsor review prior to submission.
| 10% Reduction |
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| 15% Reduction |
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| SBP 0.75 minutes after Bolus 1 |
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| SBP 1 minute after Bolus 1 |
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| SBP 1.5 minutes after Bolus 1 |
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| SBP 2 minutes after Bolus 1 |
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| SBP 3 minutes after Bolus 1 |
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| SBP 5 minutes after Bolus 1 |
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| SBP 7 minutes after Bolus 1 |
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| SBP 15 minutes after Bolus 1 |
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| Time to 90% recovery in SBP |
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