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Clevidipine in the Treatment of Blood Pressure in Patients With Acute Heart Failure (PRONTO) (PRONTO)

Primary Purpose

Hypertension, Heart Failure

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Clevidipine

Standard of Care IV antihypertensive

About this trial

This is an interventional treatment trial for Hypertension focused on measuring Hypertension, Antihypertensive Agent, Calcium Channel Blocker

Eligibility Criteria

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

Inclusion Criteria:

Age 18 years or older
Presentation consistent with acute heart failure and pulmonary congestion on physical examination as evidenced by rales
Baseline systolic blood pressure (immediately prior to initiation of study drug) of ≥160 mm Hg
Dyspnea score (sitting) of at least 5 on a 10 cm visual analog scale (VAS)
Required IV antihypertensive therapy to lower blood pressure
Written informed consent

Exclusion Criteria:

Administration of an agent (IV or oral) for the treatment of elevated BP within the previous 2 hours of randomization. (Previous short-acting non-IV nitrates, continuous positive airway pressure (CPAP), and bi-level positive airway pressure (BiPAP) were permitted)
Chest pain and/or electrocardiogram with ST segment changes consistent with acute coronary syndrome
Known or suspected aortic dissection
Acute myocardial infarction within the prior 14 days
Dialysis-dependant renal failure
Requirement for immediate endotracheal intubation
Positive pregnancy test, known pregnancy or breast feeding female
Intolerance or allergy to calcium channel blockers
Allergy to soybean oil or egg lecithin
Known liver failure, cirrhosis or pancreatitis
Prior directives against advanced life support
Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of enrollment

Sites / Locations

Jackson Hospital
Centinela Hospital
Louisiana State University Health Sciences Center
Louisiana State University Health Sciences Center - Emergency Medicine
Washington University School of Medicine
Stony Brook University and Medical Center
Duke University Medical Center
University of Cincinnati
The Cleveland Clinic
Hopial AP-HP Hotel-Dieu
Hopital AP-HP La Pitie Sapetriere
Hopital AP-HP Lariboisiere Urgencies-SMUR
Charité - Universitätsmedizin Berlin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Clevidipine

Standard of Care IV antihypertensive

Arm Description

Clevidipine (0.5 mg/mL in 20% lipid emulsion) was administered intravenously via a single dedicated line to all patients randomized to the clevidipine arm. Clevidipine was infused at an initial rate of 2 mg/h for the first 3 minutes. If blood pressure was not in the target range at 3 minutes, clevidipine was titrated to effect thereafter by doubling the dose every 3 min, per physician discretion and as tolerated by the patient until the desired effect until the SBP target range was attained. Once target range was achieved, the infusion rate could be increased or decreased as needed to maintain blood pressure for minimum of 30 minutes and a maximum duration of 96 hours. The minimum infusion rate was 1 mg/h and maximum infusion rate was 32 mg/h.

For patients randomized to standard of care (SOC) IV antihypertensive treatment, a continuous infusion of an intravenous antihypertensive agent represented standard of care. The selection of treatment was at the discretion of the investigator. The infusion was to be administered according to the institution's treatment practice.

Outcomes

Primary Outcome Measures

Time to First Achieve Initial Prespecified SBP Target Range and 15% Reduction From Baseline Within First 30 Minutes

Time to first achieve the initial pre-specified systolic blood pressure (SBP) target range and a 15% SBP reduction from baseline is the time in minutes between the initiation of study medication and the time the patient first achieved both components. Median time was estimated using Kaplan Meier method. 95% two-sided confidence interval of the median time is from 'Simon and Lee, 1982'. If patients did not reach both components within 30 minutes from the initial treatment with study medication, or another antihypertensive agent was administered, the patient was censored at 30 minutes or the time when another antihypertensive agent is given, whichever came first.

Percentage to First Achieve Initial Prespecified SBP Target Range [≥20 mm Hg and ≤40 mm Hg Apart] and 15% Reduction From Baseline Within First 30 Minutes

Analysis of the percentage of patients achieving both components of this composite endpoint (attainment of the initial prespecified SBP target range and a 15% reduction in SBP from baseline) was calculated within each treatment group using the number of mITT patients achieving the SBP reduction goal divided by the number of mITT patients, and multiplied by 100.

Secondary Outcome Measures

Percentage Reaching Prespecified Target Range Without Falling Below Lower Limit of Target Range Within First 30 Minutes

The percentage of patients reaching this endpoint was calculated within each treatment group using the number of mITT patients reaching the endpoint divided by the number of mITT patients, and multiplied by 100. Two-tailed 95% CIs were computed for these percentages.

SBP Area Under the Curve (AUC) Outside Prespecified Target Range

The magnitude and duration of SBP excursions was calculated as the area under the curve (AUC) for each patient, using the trapezoidal rule, related to time (in minutes) that each patient's SBP was outside the target range. AUC was determined based on data collected from the initiation of study medication through the end of monotherapy treatment up to 96 hours, normalized per hour, and expressed as mmHg × minute/hour.

Percentage Falling Below Lower Limit of SBP Target Range Within First 30 Minutes

The percentage of patients in whom the SBP fell below the lower limit of the prespecified target range at any time during the first 30 minutes was calculated within each treatment group using the number of mITT patients achieving the endpoint divided by the number of mITT patients and multiplied by 100. Two-tailed 95% CIs were computed for these percentages.

Percentage Falling Below Lower Limit of SBP Target Range at Any Time During Study

The percentage of patients in whom the SBP fell below the lower limit of the prespecified target range at any time during the entire study drug treatment period (up to 96 hours) was calculated within each treatment group using the number of mITT patients achieving the endpoint divided by the number of mITT patients and multiplied by 100. Two-tailed 95% CIs were computed for these percentages.

Change From Baseline in Dyspnea (Measured By VAS) at Each Time Point

A validated visual analog scale (VAS) with a horizontal ruler showing increments from 0 to 100 mm with 0 = Best and 100 = Worst was used. The test was asked from the patient's perspective and had to be administered with patient sitting. Relative change in VAS from baseline is the value at each time point minus the baseline value. Relative change from baseline was summarized descriptively (with associated two-tailed 95% CIs of the mean values) at 15, 30 and 45 minutes and at 1, 2, 3 hours and 12 hours, and 1 hour post termination of study drug treatment.

Time to Use Other IV Antihypertensives During the Study Drug Administration

The length of time to use other IV antihypertensive agents was defined as the duration in hours from the initiation of study drug through the time when any other concomitant IV antihypertensive agent was administered, thus, representing the time period without use of any other concomitant IV antihypertensive agent. Median time to use other IV antihypertensive agents was obtained using Kaplan-Meier method. If a patient did not receive any concomitant IV antihypertensive during the 96-hour treatment period, this patient was considered censored at 96 hours. If study drug was stopped less than 96 hours and the patient has no concomitant IV antihypertensive agent, the patient was considered censored when study drug was stopped.

Percentage of Patients Who Received Any Alternative IV Antihypertensive Drug at Any Time During Study Drug Treatment

The percentage of patients who received any alternative IV antihypertensive drug at any time during the study drug treatment period (up to 96 hours) was calculated using mITT patients within each treatment group.

Percentage of Patients With at Least One Episode of SBP < 90 mm Hg During Study Drug Administration (up to 96 Hours)

The percent of patients with at least one episode of SBP <90 mm Hg was calculated as the number of mITT patients who had at least one episode of SBP<90 mm Hg during study drug administration up to 96 hours divided by mITT patients, and multiplied by 100 for each treatment group.

Number of Patients That Require Intubation During Study Drug Administration up to 96 Hours

The number of patients requiring intubation was calculated based on the total number of mITT patients.

Full Information

NCT ID

NCT00803634

First Posted

December 3, 2008

Last Updated

August 21, 2014

Sponsor

The Medicines Company

1. Study Identification

Unique Protocol Identification Number

NCT00803634

Brief Title

Clevidipine in the Treatment of Blood Pressure in Patients With Acute Heart Failure (PRONTO)

Acronym

PRONTO

Official Title

A Safety and Efficacy Study of Blood Pressure Control in Acute Heart Failure - A Pilot Study (PRONTO)

Study Type

Interventional

2. Study Status

Record Verification Date

August 2014

Overall Recruitment Status

Completed

Study Start Date

December 2008 (undefined)

Primary Completion Date

February 2012 (Actual)

Study Completion Date

March 2012 (Actual)

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 was to evaluate the efficacy and safety of intravenous (IV) clevidipine as compared with standard of care IV antihypertensive agents for blood pressure (BP) lowering in patients with acute heart failure and elevated BP.

Detailed Description

This study was an open-label randomized efficacy and safety pilot trial in patients with acute heart failure (AHF) and hypertension (systolic blood pressure [SBP] ≥160 mm Hg) requiring parenteral antihypertensive therapy. Eligible patients were randomized to receive clevidipine or standard of care (SOC) intravenous antihypertensive treatment in an open-label manner in a ratio of 1:1. At the time of randomization, a patient-specific, prespecified SBP target range was determined and be recorded, prior to study drug treatment. Information on the dosing regimen, use of additional or alternative agents and transition to oral therapy if needed is detailed in the study 'ARM' and 'INTERVENTION' sections. A Data Safety Monitoring Board was utilized periodically throughout the study to monitor the safety of patients. Adverse events were assessed for 7 days post-study randomization or hospital discharge, whichever occured first. Serious adverse events (SAEs) were assessed for 30 days following study randomization. Subjects were contacted by telephone or in person up to 5 days after their 30-day time point to determine if any SAEs occurred following study drug treatment and to follow up on the Heath Economic assessments.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypertension, Heart Failure

Keywords

Hypertension, Antihypertensive Agent, Calcium Channel Blocker

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

117 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Clevidipine

Arm Type

Experimental

Arm Description

Arm Title

Standard of Care IV antihypertensive

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Clevidipine

Other Intervention Name(s)

Cleviprex, clevidipine emulsion, clevidipine injectible emulsion

Intervention Description

Clevidipine was to be administered continuously as monotherapy during the first 30 minutes. Use of an alternative IV antihypertensive agent(s) was discouraged and was limited to where medically necessary to maintain patient safety. Patients who received an alternative antihypertensive agent along with the study drug were allowed to continue in the study. If transition to an oral antihypertensive agent was required, it was to be administered approximately 1 hour prior to the termination of clevidipine with study drug down-titrated or terminated in order to maintain the desired blood pressure level.

Intervention Type

Drug

Intervention Name(s)

Standard of Care IV antihypertensive

Other Intervention Name(s)

nitroglycerin, nicardipine, sodium nitroprusside, isosorbide dinitrate, hydralizine, diltiazem

Intervention Description

SOC IV antihypertensive agent will be administered for a minimum of 30 min and, if medically warranted, may continue beyond 96 hours at the investigator's discretion. As with clevidipine, the SOC agent was to be administered continuously as monotherapy during the first 30 minutes. Use of an alternative agent(s) was discouraged and was limited to where medically necessary to maintain patient safety. Higher dose titration rates were required to be attempted prior to making the decision to switch to or add on an alternative antihypertensive agent(s). Patients who received an alternative antihypertensive agent with SOC were allowed to continue in the study. If transition to an oral antihypertensive agent was required, it was to be administered per institutional practice.

Primary Outcome Measure Information:

Title

Time to First Achieve Initial Prespecified SBP Target Range and 15% Reduction From Baseline Within First 30 Minutes

Description

Time Frame

Initiation of study drug through the initial 30-minutes

Title

Percentage to First Achieve Initial Prespecified SBP Target Range [≥20 mm Hg and ≤40 mm Hg Apart] and 15% Reduction From Baseline Within First 30 Minutes

Description

Time Frame

Initiation of study drug through the initial 30-minutes

Secondary Outcome Measure Information:

Title

Percentage Reaching Prespecified Target Range Without Falling Below Lower Limit of Target Range Within First 30 Minutes

Description

Time Frame

Initiation of study drug through the initial 30-minutes

Title

SBP Area Under the Curve (AUC) Outside Prespecified Target Range

Description

Time Frame

Initiation of study drug through end of monotherapy (up to 96 hours)

Title

Percentage Falling Below Lower Limit of SBP Target Range Within First 30 Minutes

Description

Time Frame

Initiation of study drug through the initial 30-minutes

Title

Percentage Falling Below Lower Limit of SBP Target Range at Any Time During Study

Description

Time Frame

Initiation through termination of study drug (up to 96 hours)

Title

Change From Baseline in Dyspnea (Measured By VAS) at Each Time Point

Description

Time Frame

Baseline (immediately prior to study drug administration) through 1 hour after study drug termination

Title

Time to Use Other IV Antihypertensives During the Study Drug Administration

Description

Time Frame

Initiation of study drug through any other concomitant IV antihypertensive agent administered, up to 96 hours

Title

Percentage of Patients Who Received Any Alternative IV Antihypertensive Drug at Any Time During Study Drug Treatment

Description

Time Frame

Initiation through termination of study drug (up to 96 hours)

Title

Percentage of Patients With at Least One Episode of SBP < 90 mm Hg During Study Drug Administration (up to 96 Hours)

Description

Time Frame

Initiation through termination of study drug (up to 96 hours)

Title

Number of Patients That Require Intubation During Study Drug Administration up to 96 Hours

Description

The number of patients requiring intubation was calculated based on the total number of mITT patients.

Time Frame

Initiation through termination of study drug (up to 96 hours)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age 18 years or older Presentation consistent with acute heart failure and pulmonary congestion on physical examination as evidenced by rales Baseline systolic blood pressure (immediately prior to initiation of study drug) of ≥160 mm Hg Dyspnea score (sitting) of at least 5 on a 10 cm visual analog scale (VAS) Required IV antihypertensive therapy to lower blood pressure Written informed consent Exclusion Criteria: Administration of an agent (IV or oral) for the treatment of elevated BP within the previous 2 hours of randomization. (Previous short-acting non-IV nitrates, continuous positive airway pressure (CPAP), and bi-level positive airway pressure (BiPAP) were permitted) Chest pain and/or electrocardiogram with ST segment changes consistent with acute coronary syndrome Known or suspected aortic dissection Acute myocardial infarction within the prior 14 days Dialysis-dependant renal failure Requirement for immediate endotracheal intubation Positive pregnancy test, known pregnancy or breast feeding female Intolerance or allergy to calcium channel blockers Allergy to soybean oil or egg lecithin Known liver failure, cirrhosis or pancreatitis Prior directives against advanced life support 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

W. Frank Peacock, MD

Organizational Affiliation

The Cleveland Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Jackson Hospital

City

Montgomery

State/Province

Alabama

ZIP/Postal Code

36106

Country

United States

Facility Name

Centinela Hospital

City

Inglewood

State/Province

California

ZIP/Postal Code

90301

Country

United States

Facility Name

Louisiana State University Health Sciences Center

City

Baton Rouge

State/Province

Louisiana

ZIP/Postal Code

70805

Country

United States

Facility Name

Louisiana State University Health Sciences Center - Emergency Medicine

City

New Orleans

State/Province

Louisiana

ZIP/Postal Code

70112

Country

United States

Facility Name

Washington University School of Medicine

City

St. Louis

State/Province

Missouri

ZIP/Postal Code

63110

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 Medical Center

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

The Cleveland Clinic

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

Facility Name

Hopial AP-HP Hotel-Dieu

City

Paris

ZIP/Postal Code

75004

Country

France

Facility Name

Hopital AP-HP La Pitie Sapetriere

City

Paris

ZIP/Postal Code

75013

Country

France

Facility Name

Hopital AP-HP Lariboisiere Urgencies-SMUR

City

Paris

ZIP/Postal Code

75475

Country

France

Facility Name

Charité - Universitätsmedizin Berlin

City

Berlin

ZIP/Postal Code

13353

Country

Germany

12. IPD Sharing Statement

Learn more about this trial

Clevidipine in the Treatment of Blood Pressure in Patients With Acute Heart Failure (PRONTO)

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