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

Primary Purpose

Dyspnea, Hypertension, Acute Heart Failure

Status
Withdrawn
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Stage 1: Clevidipine (double-blinded)
Stage 1: Placebo (double-blinded)
Stage 2: Clevidipine (open-label)
Stage 2: Standard of Care (open-label)
Sponsored by
The Medicines Company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Dyspnea

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Drug Research and Analysis Corporation/Jackson Hospital
  • University of Arizona Medical Center
  • Washington University School of Medicine
  • New York Methodist Hospital
  • Maimonides Medical Center
  • Stony Brook University and Medical Center
  • Duke University Hospital
  • University of Cincinnati
  • Baylor College of Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Active Comparator

Arm Label

Stage 1: Clevidipine (double-blinded)

Stage 1: Placebo (double-blinded)

Stage 2: Clevidipine (open-label)

Stage 2: Standard of Care (open-label)

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Change in dyspnea VAS score from baseline at 3 hours post-baseline

Secondary Outcome Measures

Median time to reach target BP within the first 30 minutes
Percentage of patients who require rescue therapy (ie, receive any alternative IV antihypertensive drug) within the first 30 minutes

Full Information

First Posted
October 12, 2020
Last Updated
October 12, 2020
Sponsor
The Medicines Company
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1. Study Identification

Unique Protocol Identification Number
NCT04592380
Brief Title
Clevidipine vs Placebo or Standard of Care for Dyspnea and Blood Pressure Control in AHF
Acronym
PRONTO II
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Withdrawn
Why Stopped
Product was divested to Chiesi USA, who decided to not move forward with study.
Study Start Date
August 2014 (undefined)
Primary Completion Date
February 2016 (Anticipated)
Study Completion Date
November 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Medicines Company

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dyspnea, Hypertension, Acute Heart Failure

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Stage 1: Clevidipine (double-blinded)
Arm Type
Experimental
Arm Description
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.
Arm Title
Stage 1: Placebo (double-blinded)
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Stage 2: Clevidipine (open-label)
Arm Type
Experimental
Arm Description
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.
Arm Title
Stage 2: Standard of Care (open-label)
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Stage 1: Clevidipine (double-blinded)
Other Intervention Name(s)
Cleviprex, clevidipine
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Stage 1: Placebo (double-blinded)
Other Intervention Name(s)
Intralipid
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Stage 2: Clevidipine (open-label)
Other Intervention Name(s)
Cleviprex, clevidipine
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Stage 2: Standard of Care (open-label)
Intervention Description
Transition to oral antihypertensive medication from SOC IV antihypertensive is per institutional practice.
Primary Outcome Measure Information:
Title
Change in dyspnea VAS score from baseline at 3 hours post-baseline
Time Frame
Immediately prior to study drug administration (baseline) to 3 hours post-baseline
Secondary Outcome Measure Information:
Title
Median time to reach target BP within the first 30 minutes
Time Frame
Study drug initiation through the first 30 minutes of study drug infusion
Title
Percentage of patients who require rescue therapy (ie, receive any alternative IV antihypertensive drug) within the first 30 minutes
Time Frame
Study drug initiation through the first 30 minutes of study drug infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William F Peacock, MD, FACEP
Organizational Affiliation
Baylor College of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Drug Research and Analysis Corporation/Jackson Hospital
City
Montgomery
State/Province
Alabama
ZIP/Postal Code
36106
Country
United States
Facility Name
University of Arizona Medical Center
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85719
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
New York Methodist Hospital
City
Brooklyn
State/Province
New York
ZIP/Postal Code
11215
Country
United States
Facility Name
Maimonides Medical Center
City
Brooklyn
State/Province
New York
ZIP/Postal Code
11219
Country
United States
Facility Name
Stony Brook University and Medical Center
City
Stony Brook
State/Province
New York
ZIP/Postal Code
11794
Country
United States
Facility Name
Duke University Hospital
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

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

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