Clevidipine vs Placebo or Standard of Care for Dyspnea and Blood Pressure Control in AHF (PRONTO II)

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)

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.

Study Overview

• Status: Withdrawn
• Conditions: Hypertension; Dyspnea; Acute Heart Failure
• Intervention / Treatment: 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)

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Montgomery, Alabama, United States, 36106
      • Drug Research and Analysis Corporation/Jackson Hospital
  • Arizona
    • Tucson, Arizona, United States, 85719
      • University of Arizona Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Brooklyn, New York, United States, 11219
      • Maimonides Medical Center
    • Brooklyn, New York, United States, 11215
      • New York Methodist Hospital
    • Stony Brook, New York, United States, 11794
      • Stony Brook University and Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

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:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stage 1: Clevidipine (double-blinded); 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); 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.; Other Names: Cleviprex; clevidipine
Placebo Comparator: Stage 1: Placebo (double-blinded); 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); 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.; Other Names: Intralipid
Experimental: Stage 2: Clevidipine (open-label); 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); 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.; Other Names: Cleviprex; clevidipine
Active Comparator: Stage 2: Standard of Care (open-label); 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); Transition to oral antihypertensive medication from SOC IV antihypertensive is per institutional practice.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: The Medicines Company
• Investigators: Principal Investigator: William F Peacock, MD, FACEP, Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Anticipated): February 1, 2016
• Study Completion (Anticipated): November 1, 2016

Study Registration Dates

• First Submitted: October 12, 2020
• First Submitted That Met QC Criteria: October 12, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Actual): October 19, 2020
• Last Update Submitted That Met QC Criteria: October 12, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Heart Failure; Dyspnea; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Soybean oil, phospholipid emulsion; Clevidipine
• Other Study ID Numbers: MDCO-CLV-13-03; PRONTO II (Other Identifier: The Medicines Company (Sponsor))