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

NCT00803634 | Completed Phase 3 Results DMC

• 1 other identifier: TMC-CLV-08-01
• Study Type: interventional
• Target: 117
• Locations: 3 countries
• Sites: 13

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.

Conditions

Hypertension; Heart Failure

Keywords

Hypertension; Antihypertensive Agent; Calcium Channel Blocker

Outcome Measures

Primary Outcomes (2)

• 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.

  Initiation of study drug through the initial 30-minutes

• 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.

  Initiation of study drug through the initial 30-minutes

Secondary Outcomes (9)

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

  Initiation of study drug through the initial 30-minutes

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

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

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

  Initiation of study drug through the initial 30-minutes

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

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

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

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

Study Arms (2)

Clevidipine

EXPERIMENTAL

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

Standard of Care IV antihypertensive

ACTIVE COMPARATOR

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

Interventions

Clevidipine DRUG

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.

Also known as: Cleviprex, clevidipine emulsion, clevidipine injectible emulsion

Clevidipine

Standard of Care IV antihypertensive DRUG

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.

Also known as: nitroglycerin, nicardipine, sodium nitroprusside, isosorbide dinitrate, hydralizine, diltiazem

Standard of Care IV antihypertensive

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The Medicines Company: lead

Study Sites (13)

Jackson Hospital

Montgomery, Alabama, 36106, United States

Location

Centinela Hospital

Inglewood, California, 90301, United States

Location

Louisiana State University Health Sciences Center

Baton Rouge, Louisiana, 70805, United States

Location

Louisiana State University Health Sciences Center - Emergency Medicine

New Orleans, Louisiana, 70112, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Stony Brook University and Medical Center

Stony Brook, New York, 11794, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45267, United States

Location

The Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Hopial AP-HP Hotel-Dieu

Paris, 75004, France

Location

Hopital AP-HP La Pitie Sapetriere

Paris, 75013, France

Location

Hopital AP-HP Lariboisiere Urgencies-SMUR

Paris, 75475, France

Location

Charité - Universitätsmedizin Berlin

Berlin, 13353, Germany

Location

MeSH Terms

Conditions

Hypertension; Heart Failure

Interventions

clevidipine; Nitroglycerin; Nicardipine; Nitroprusside; Isosorbide Dinitrate; Diltiazem

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Heart Diseases

Intervention Hierarchy (Ancestors)

Nitro Compounds; Organic Chemicals; Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Ferricyanides; Cyanides; Anions; Ions; Electrolytes; Inorganic Chemicals; Ferric Compounds; Iron Compounds; Hydrogen Cyanide; Nitrogen Compounds; Isosorbide; Sorbitol; Sugar Alcohols; Alcohols; Carbohydrates; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Jason Campagna
• Organization: The Medicines Company

jason.campagna@themedco.com

973-290-6199

Study Officials

• W. Frank Peacock, MD

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 3, 2008
• First Posted: December 5, 2008
• Study Start: December 1, 2008
• Primary Completion: February 1, 2012
• Study Completion: March 1, 2012
• Last Updated: August 29, 2014
• Results First Posted: August 19, 2014

Record last verified: 2014-08

Locations

DE (1); US (9); FR (3)