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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
The Medicines Company
ClinicalTrials.gov Identifier:
NCT00803634
First received: December 3, 2008
Last updated: August 21, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Hypertension
Heart Failure
Drug: Clevidipine
Drug: Standard of Care IV antihypertensive
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Safety and Efficacy Study of Blood Pressure Control in Acute Heart Failure - A Pilot Study (PRONTO)

Resource links provided by NLM:


Further study details as provided by The Medicines Company:

Primary Outcome Measures:
  • Time to First Achieve Initial Prespecified SBP Target Range and 15% Reduction From Baseline Within First 30 Minutes [ Time Frame: Initiation of study drug through the initial 30-minutes ] [ Designated as safety issue: No ]
    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 [ Time Frame: Initiation of study drug through the initial 30-minutes ] [ Designated as safety issue: No ]
    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 [ Time Frame: Initiation of study drug through the initial 30-minutes ] [ Designated as safety issue: No ]
    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 [ Time Frame: Initiation of study drug through end of monotherapy (up to 96 hours) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Initiation of study drug through the initial 30-minutes ] [ Designated as safety issue: No ]
    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 [ Time Frame: Initiation through termination of study drug (up to 96 hours) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline (immediately prior to study drug administration) through 1 hour after study drug termination ] [ Designated as safety issue: No ]
    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 [ Time Frame: Initiation of study drug through any other concomitant IV antihypertensive agent administered, up to 96 hours ] [ Designated as safety issue: No ]
    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 [ Time Frame: Initiation through termination of study drug (up to 96 hours) ] [ Designated as safety issue: No ]
    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) [ Time Frame: Initiation through termination of study drug (up to 96 hours) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Initiation through termination of study drug (up to 96 hours) ] [ Designated as safety issue: No ]
    The number of patients requiring intubation was calculated based on the total number of mITT patients.


Enrollment: 117
Study Start Date: December 2008
Study Completion Date: March 2012
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Clevidipine
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.
Drug: Clevidipine
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.
Other Names:
  • Cleviprex
  • clevidipine emulsion
  • clevidipine injectible emulsion
Active Comparator: Standard of Care IV antihypertensive
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.
Drug: Standard of Care IV antihypertensive
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.
Other Names:
  • nitroglycerin
  • nicardipine
  • sodium nitroprusside
  • isosorbide dinitrate
  • hydralizine
  • diltiazem

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00803634

Locations
United States, Alabama
Jackson Hospital
Montgomery, Alabama, United States, 36106
United States, California
Centinela Hospital
Inglewood, California, United States, 90301
United States, Louisiana
Louisiana State University Health Sciences Center
Baton Rouge, Louisiana, United States, 70805
Louisiana State University Health Sciences Center - Emergency Medicine
New Orleans, Louisiana, United States, 70112
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, New York
Stony Brook University and Medical Center
Stony Brook, New York, United States, 11794
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
University of Cincinnati
Cincinnati, Ohio, United States, 45267
The Cleveland Clinic
Cleveland, Ohio, United States, 44195
France
Hopital AP-HP Lariboisiere Urgencies-SMUR
Paris, France, 75475
Hopial AP-HP Hotel-Dieu
Paris, France, 75004
Hopital AP-HP La Pitie Sapetriere
Paris, France, 75013
Germany
Charité - Universitätsmedizin Berlin
Berlin, Germany, 13353
Sponsors and Collaborators
The Medicines Company
Investigators
Principal Investigator: W. Frank Peacock, MD The Cleveland Clinic
  More Information

No publications provided

Responsible Party: The Medicines Company
ClinicalTrials.gov Identifier: NCT00803634     History of Changes
Other Study ID Numbers: TMC-CLV-08-01, TMC-CLV-08-01
Study First Received: December 3, 2008
Results First Received: June 3, 2014
Last Updated: August 21, 2014
Health Authority: United States: Food and Drug Administration
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Switzerland: Swissmedic

Keywords provided by The Medicines Company:
Hypertension
Antihypertensive Agent
Calcium Channel Blocker

Additional relevant MeSH terms:
Heart Failure
Hypertension
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Antihypertensive Agents
Nicardipine
Nitroprusside
Calcium Channel Blockers
Clevidipine
Isosorbide-5-mononitrate
Nitroglycerin
Isosorbide Dinitrate
Isosorbide
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Nitric Oxide Donors

ClinicalTrials.gov processed this record on August 28, 2014