Clevidipine vs Placebo or Standard of Care for Dyspnea and Blood Pressure Control in AHF

Study Overview
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Brief Summary
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The purpose of this study is to evaluate dyspnea improvement and other parameters of efficacy and safety in acute heart failure (AHF) patients receiving an intravenous (IV) infusion of clevidipine in comparison to standard of care (SOC) and placebo.

Detailed Description
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Randomization will occur in two stages. Stage 1 patients will be randomized in a double-blinded manner in a 1:1 ratio to receive either clevidipine or placebo IV infusion. Upon completion of Stage 1, Stage 2 patients will be randomized in an open-label manner in a 1:1 ratio to receive either clevidipine or standard of care (SOC) IV infusion. At the time of randomization, a patient-specific, prespecified systolic blood pressure (SBP) target range will be determined and recorded prior to study drug treatment. Up to 500 patients may be enrolled to achieve a total of 100 Stage 1 and 300 Stage 2 patients with confirmed AHF per protocol. A Data Safety Monitoring Board will be utilized periodically throughout the study to monitor the safety of patients. Adverse events will be assessed for 7 days post-study randomization or hospital discharge, whichever occurred sooner. Serious adverse events (SAEs) were assessed for 30 days following study randomization.

Official Title
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A Randomized Parallel Group Controlled Comparison Study of Clevidipine Versus Placebo or Standard of Care for Dyspnea and Blood Pressure Control in Acute Heart Failure (PRONTO II)

Conditions
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Dyspnea, Hypertension, Acute Heart Failure

Intervention / Treatment
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* Drug: Stage 1: Clevidipine (double-blinded)
* Drug: Stage 1: Placebo (double-blinded)
* Drug: Stage 2: Clevidipine (open-label)
* Drug: Stage 2: Standard of Care (open-label)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older and providing Presentation consistent with AHF as manifest by pulmonary congestion Dyspnea score (sitting) ≥ 50 mm on a 100 mm visual analog scale In Stage 1, baseline SBP ≥130 - 160 mmHg (measured immediately prior to initiation of study drug); in Stage 2, baseline SBP ≥ 130 mmHg Exclusion Criteria: Administration of an IV or oral antihypertensive agent within the previous 2 hours of randomization (short acting oral or sublingual nitrates are permitted) Chest pain and/or electrocardiogram (ECG) with ST segment changes consistent with acute coronary syndrome Known or suspected aortic dissection Acute myocardial infarction (AMI) within the prior 14 days Dialysis-dependent renal failure Requirement for immediate endotracheal intubation Suspected pregnancy or breast feeding female Intolerance or allergy to calcium channel blockers Allergy to soybean oil or lecithin Known liver failure, cirrhosis or pancreatitis 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
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: Clevidipine (double-blinded)<br>Clevidipine (0.5 mg/mL in 20% lipid emulsion) will be administered in a double-blinded fashion intravenously to all patients randomized to the clevidipine arm in Stage 1. Clevidipine will be initiated at an initial rate of 2 mg/h for the first 1.5 minutes (90 seconds) and titrated thereafter per the Food and Drug Administration (FDA) approved clevidipine label, to achieve the target SBP +/- 5 mmHg. If the target SBP is achieved at any of the titration doses, that rate may be continued for up to 24 hours. If the desired BP lowering effect is not attained within 30 minutes or not maintained thereafter, any alternative antihypertensive agent may be used per institutional treatment practice, with or without stopping the study drug infusion. | Drug: Stage 1: Clevidipine (double-blinded)<br>* Patients may be transitioned to an oral antihypertensive medication as necessary. When such a transition is required, then approximately 1 hour prior to the anticipated cessation of the double-blinded clevidipine infusion, an oral antihypertensive agent may be administered. The clevidipine infusion may be down-titrated or terminated at any time following administration of the oral agent, in order to achieve the desired BP level.<br>* Other names: clevidipine;|
| Placebo Comparator: Stage 1: Placebo (double-blinded)<br>Placebo will be administered in a double-blinded fashion intravenously to all patients randomized to the clevidipine arm in Stage 1. Placebo will be initiated at an initial rate of 2 mg/h for the first 1.5 minutes (90 seconds) and titrated thereafter according to the same dosing instructions as for clevidipine to achieve the target SBP +/- 5 mmHg. If the target SBP is achieved at any of the titration doses, that rate may be continued for up to 24 hours. If the desired BP lowering effect is not attained within 30 minutes or not maintained thereafter, any alternative antihypertensive agent may be used per institutional treatment practice, with or without stopping the study drug infusion. | Drug: Stage 1: Placebo (double-blinded)<br>* Patients may be transitioned to an oral antihypertensive medication as necessary. When such a transition is required, then approximately 1 hour prior to the anticipated cessation of the double-blinded placebo infusion, an oral antihypertensive agent may be administered. The placebo infusion may be down-titrated or terminated at any time following administration of the oral agent, in order to achieve the desired BP level.<br>* Other names: Intralipid;|
| Experimental: Stage 2: Clevidipine (open-label)<br>Clevidipine (0.5 mg/mL in 20% lipid emulsion) will be administered in an open-label fashion intravenously to all patients randomized to the clevidipine arm in Stage 2, following the same dosing instructions as in the clevidipine arm in Stage 1. If the desired BP lowering effect is not attained within 30 minutes or not maintained thereafter, any alternative antihypertensive agent may be used per institutional treatment practice, with or without stopping the study drug infusion. | Drug: Stage 2: Clevidipine (open-label)<br>* Patients may be transitioned to an oral antihypertensive medication as necessary. When such a transition is required, then approximately 1 hour prior to the anticipated cessation of the clevidipine infusion, an oral antihypertensive agent may be administered. The clevidipine infusion may be down-titrated or terminated at any time following administration of the oral agent, in order to achieve the desired BP level.<br>* Other names: clevidipine;|
| Active Comparator: Stage 2: Standard of Care (open-label)<br>For patients randomized to SOC, the infusion must be continuous, administered per the institution's treatment practice, and dose titration must be performed to a maximum allowed or maximum tolerated dose to achieve target SBP. If treatment with an alternative IV anti-hypertensive agent is required, the patient will be transitioned to an alternative IV antihypertensive agent according to the institutional standard of care. | Drug: Stage 2: Standard of Care (open-label)<br>* Transition to oral antihypertensive medication from SOC IV antihypertensive is per institutional practice.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in dyspnea VAS score from baseline at 3 hours post-baseline |  | Immediately prior to study drug administration (baseline) to 3 hours post-baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median time to reach target BP within the first 30 minutes |  | Study drug initiation through the first 30 minutes of study drug infusion | 
| Percentage of patients who require rescue therapy (ie, receive any alternative IV antihypertensive drug) within the first 30 minutes |  | Study drug initiation through the first 30 minutes of study drug infusion |