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

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ClinicalTrials.gov Identifier: NCT00803634
Recruitment Status : Completed
First Posted : December 5, 2008
Results First Posted : August 19, 2014
Last Update Posted : August 29, 2014
Sponsor:
Information provided by (Responsible Party):
The Medicines Company

Tracking Information
First Submitted Date  ICMJE December 3, 2008
First Posted Date  ICMJE December 5, 2008
Results First Submitted Date  ICMJE June 3, 2014
Results First Posted Date  ICMJE August 19, 2014
Last Update Posted Date August 29, 2014
Study Start Date  ICMJE December 2008
Actual Primary Completion Date February 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 30, 2014)
  • 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 ]
    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 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 4, 2008)
Median time and percent of patients that attain the initial prespecified SBP target range (minimum of 20 mm Hg and a maximum of 40 mm Hg apart) and a 15% reduction in SBP from baseline within the first 30 minutes [ Time Frame: Within initial 30-minute treatment period ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 30, 2014)
  • 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 ]
    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) ]
    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 ]
    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) ]
    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 ]
    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 ]
    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) ]
    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) ]
    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) ]
    The number of patients requiring intubation was calculated based on the total number of mITT patients.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 4, 2008)
  • The percentage of patients who reach the prespecified SBP target range without falling below the lower limit of the prespecified target range during the first 30 minute treatment period [ Time Frame: First 30-minute treatment period ]
  • Magnitude and duration of SBP excursions (calculated as area under the curve) outside the target range(s) normalized per hour for the duration of the study drug administration up to 96 hours [ Time Frame: Duration of study drug administration up to 96 hours ]
  • The percentage of patients in whom the SBP falls below the lower limit of the prespecified target range at any time during the first 30 minutes and below the target range at any time during the entire study drug treatment period up to 96 hours [ Time Frame: Study drug treatment period, up to 96 hours ]
  • Change from baseline in the dyspnea scores (Visual Analogue Score, Vasodilatation in the Management of Acute Congestive Heart Failure, and Provocative Dyspnea Assessment) at each time point [ Time Frame: Up to 1 hour post-termination of study drug treatment ]
  • Length of time on study drug without using any other concomitant IV antihypertensive agent up to 96 hours [ Time Frame: Up to 96 hours ]
  • Percentage of patients who receive any alternative IV antihypertensive drug at any time during the study drug treatment period up to 96 hours [ Time Frame: Up to 96 hours ]
  • Number of episodes and percent time the SBP < 90 mm Hg during study drug administration up to 96 hours [ Time Frame: Up to 96 hours ]
  • Number of patients that require intubation during study drug administration up to 96 hours [ Time Frame: Up to 96 hours ]
  • Safety of a prolonged infusion of study drug assessed according to clinical laboratory parameters, and adverse events and SAEs up to 7 days or discharge whichever occurs first and SAEs through 30 days from randomization into the study [ Time Frame: AEs will be assessed up to 7 days or discharge, whichever occurs first following randomization. SAEs will be assessed for 30 days following randomization. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clevidipine in the Treatment of Blood Pressure in Patients With Acute Heart Failure (PRONTO)
Official Title  ICMJE A Safety and Efficacy Study of Blood Pressure Control in Acute Heart Failure - A Pilot Study (PRONTO)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hypertension
  • Heart Failure
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Clevidipine
  • 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.
    Intervention: Drug: Standard of Care IV antihypertensive
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 6, 2012)
117
Original Estimated Enrollment  ICMJE
 (submitted: December 4, 2008)
140
Actual Study Completion Date  ICMJE March 2012
Actual Primary Completion Date February 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Germany,   United States
Removed Location Countries Switzerland,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT00803634
Other Study ID Numbers  ICMJE TMC-CLV-08-01
TMC-CLV-08-01 ( Other Identifier: Sponsor )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party The Medicines Company
Study Sponsor  ICMJE The Medicines Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: W. Frank Peacock, MD The Cleveland Clinic
PRS Account The Medicines Company
Verification Date August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP