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Nebulized Inhaled Milrinone in a Hospitalized Advanced Heart Failure Population (iMilrinone)

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ClinicalTrials.gov Identifier: NCT02077010
Recruitment Status : Not yet recruiting
First Posted : March 4, 2014
Last Update Posted : January 11, 2019
Sponsor:
Collaborator:
University of Kansas
Information provided by (Responsible Party):
Zachary L. Cox, Vanderbilt University Medical Center

Brief Summary:

Patients with end stage heart failure have significant symptoms (including fatigue and shortness of breath) which prevent them from being able to perform most activities of daily living. Milrinone is one of the inotropic medications that has been studied and used in the treatment of end stage heart failure. End stage heart failure patients awaiting a heart transplantation often have to be maintained on IV milrinone 24 hours a day through a chronic IV line. Two problems arise with this therapy. First, the IV line itself creates an opportunity for infection and blood clots, in addition to interfering with patient's quality of life. Second, patients may be exposed to higher levels of milrinone when given IV than are necessary for maintaining their heart's function.

The investigators goal is to show that inhaled milrinone is equivalent to "standard of care" IV milrinone in improving heart and lung pressures in end stage heart failure patients (who respond to milrinone therapy) in a prospective, randomized, controlled clinical trial. Patients who are sent for a right heart catheterization procedure by their cardiologist to determine if they require milrinone will be randomly chosen to be in the continuous IV milrinone group or the inhaled milrinone group after agreeing to participate in this study. Patients in the inhaled milrinone group will receive 60mg in 4ml of fluid inhaled by a jet nebulizer every 8 hours. Patients in the IV arm will receive a constant IV infusion rate. Both groups will have a standard-of-care repeat right heart catheterization procedure an average of 48- 96 hours after milrinone initiation to evaluate their response to milrinone. Afterward, all patients that respond will be placed on the standard of care IV milrinone for the duration of their therapy, as directed by their cardiologist.


Condition or disease Intervention/treatment Phase
Heart Failure Cardiomyopathy Drug: Milrinone Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nebulized Inhaled Milrinone in a Hospitalized Advanced Heart Failure Population: A Randomized Controlled Trial
Estimated Study Start Date : April 1, 2019
Estimated Primary Completion Date : December 1, 2019
Estimated Study Completion Date : January 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: Inhaled nebulized milrinone
Inhaled nebulized milrinone 60mg/4ml every 8 hours using a vibrating mesh nebulizer
Drug: Milrinone
Milrinone is both the active comparison and experimental arm. The intervention arm will receive milrinone via inhalation of a nebulizer solution. The active comparison arm will receive milrinone via a continuous intravenous infusion.
Other Name: Primacor

Active Comparator: Intravenous milrinone
Continuously infused IV milrinone at 0.375mcg/kg/min
Drug: Milrinone
Milrinone is both the active comparison and experimental arm. The intervention arm will receive milrinone via inhalation of a nebulizer solution. The active comparison arm will receive milrinone via a continuous intravenous infusion.
Other Name: Primacor




Primary Outcome Measures :
  1. Change in pulmonary capillary wedge pressure (PCWP) and Cardiac Index (CI) hemodynamics from baseline to second right heart catheterization [ Time Frame: Right heart catheterization will be performed at baseline to determine need for milrinone initiation. A second right heart catheterization will be performed 48 -96 hours after initiation of IV or inhaled milrinone. ]
    We will compare, in each arm, the baseline hemodynamics of RHC to the hemodynamics from the 2nd RHC, assessing if a greater than or equal to a 20% decrease in PCWP or greater than or equal to a 20% increase in CI has occurred.

  2. Change in Cardiac Index (CI) using Central Venous Catheter [ Time Frame: Right heart catheterization will be performed at baseline to determine need for milrinone initiation. A centrally measured SVO2 from a central venous catheter will be obtained at 48-96hrs from baseline in lieu of a RHC if RHC is not performed. ]
    centrally (ie: PICC access) measured SVO2 which will be used to determine Fick calculation of CI (a >20% increase in CI will be required to meet primary end point compared to Fick CI from baseline) without need for PA catheter placement

  3. Natriuretic Peptide and Dyspnea visual analog scale changes [ Time Frame: NAtriurietic peptide and a dyspnea score via a patient reported dyspnea visual analog scale will be measured at baseline and compared to the final measurements at 48-96hrs if RHC or central venous SVO2 is not available ]
    in the absence of PA catheter placement and central access for SVO2 determination, a > 30% decline in laboratory based BNP measurements compared to baseline BNP (21) and an improvement of 15 percentage points from baseline in the dyspnea visual analog scale (range 0-100) will also be considered to meet primary endpoint.


Secondary Outcome Measures :
  1. Hemodynamic assessment at repeat right heart catheterization [ Time Frame: Right heart catheterization will be performed at baseline to determine need for milrinone initiation. A second right heart catheterization will be performed an average of 48 hours after initiation of IV or inhaled milrinone. ]
    Change in RHC hemodynamic variables and RV stroke work index and mixed venous oxygen saturation compared to pre-milrinone RHC values

  2. Pharmacokinetic analysis of drug exposure between IV and inhaled milrinone [ Time Frame: Plasma milrinone levels will be determined from 4 blood samples obtained at 30 minutes after 1st dose, prior to second and fourth doses, and 30 min after 5th dose in the inhaled arm and at 6, 12, 24, and 48 hrs in the IV milrinone arm. ]

    Pharmacokinetic profile assessment of inhaled versus IV milrionone including area under the curve (AUC) for total drug exposure.

    IV milrinone Arm: plasma samples at 6, 12, 24, and 48 hours after starting therapy Inhlaed milrinone Arm: plasma samples will be drawn at: 0.5 hour after first inhaled treatment, prior to the second inhaled treatment dose, before the 7th inhaled dose, 0.5 hour after the 7th inhaled dose


  3. Adverse event rates including hypotension and arrhythmias [ Time Frame: From date of randomization until study drug is completed (less than or equal to 72 hr after randomization) ]

    General adverse event (AE) rates were graded according to National Institutes of Health - Common Terminology Criteria for Adverse Events (CTCAE) and specific AE such as hypotension and arrhythmias defined as:

    1. Hypotension: systolic blood pressure (SBP) < 80mmHg (milimeters mercury) for > 30min or symptomatic hypotension necessitating clinical intervention (See withdrawal criteria for details)
    2. Arrhythmias: "New" atrial or ventricular arrhythmias lasting > 30 seconds or any arrhythmia causing hemodynamic instability requiring intervention

  4. Adverse event rate by glomerular filtration rate [ Time Frame: From date of randomization until study drug is completed (less than or equal to 72 hr after randomization) ]
    Patient adverse event (AE) rates stratified by baseline glomerular filtration rate (GFR) < 40ml/min versus GFR > 40ml/min

  5. Plasma concentrations of milrinone in therapeutic range [ Time Frame: At steady state, which will be the plasma sample 48 hrs after starting IV milrinone and the plasma concentration 0.5hrs after the 7th inhaled dose in the inhalation arm ]
    Percent achievement of steady state milrinone plasma concentrations in the therapeutic range (100-300ng/ml) for each study group

  6. All cause mortality [ Time Frame: From date of randomization until study drug is completed (less than or equal to 72 hr after randomization) ]
    Death from any cause during the study period


Other Outcome Measures:
  1. Study Withdrawal Criteria -1 [ Time Frame: From date of randomization until study drug is completed (less than or equal to 96 hr after randomization) ]
    Hypersensitivity reaction to milrinone: Systemic hypotension (MAP < 60 mmHg for > 30 minutes) plus one of the following: bronchospasm (clinical wheezing) or rash (any type) / urticaria (any type)

  2. Withdrawal criteria - 2 [ Time Frame: From date of randomization until study drug is completed (less than or equal to 96 hr after randomization) ]
    Acute respiratory failure requiring intubation and mechanical ventilation that is temporally related to inhaled milrinone delivery

  3. Withdrawal criteria - 3 [ Time Frame: From date of randomization until study drug is completed (less than or equal to 96 hr after randomization) ]
    Deterioration of heart failure by the treating cardiologist's clinical assessment that necessitates additional inotrope/vasopressor support (defined as continuous infusion of dobutamine or dopamine at the time of second right heart catheterization and or assessment of primary outcome)

  4. Withdrawal criteria -4 [ Time Frame: From date of randomization until study drug is completed (less than or equal to 96 hr after randomization) ]
    Deterioration of heart failure by the treating cardiologists clinical assessment that necessitates additional vasopressor medication support (defined as use of ANY norepinephrine, epinephrine or phenylephrine).

  5. Withdrawal criteria -5 [ Time Frame: From date of randomization until study drug is completed (less than or equal to 96 hr after randomization) ]
    Deterioration of heart failure by the treating cardiologists clinical assessment that necessitates emergent temporary or durable mechanical circulatory support (ECMO, Impella or LVAD)

  6. Withdrawal criteria -6 [ Time Frame: From date of randomization until study drug is completed (less than or equal to 96 hr after randomization) ]
    Attending heart failure cardiologist decision at anytime during the study (necessitates discussion with site primary investigator)

  7. Withdrawal criteria -7 [ Time Frame: From date of randomization until study drug is completed (less than or equal to 96 hr after randomization) ]
    Patient choice at anytime during the study duration



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients age > 18 years old
  2. Symptomatic Stage D heart failure requiring initiation of inotropic medication at the discretion of their cardiologist
  3. Signed informed consent

Exclusion Criteria:

  1. Patients incapable of signing informed consent for any reason
  2. Patients who are pregnant or breastfeeding
  3. Systolic blood pressure less than 85 mmHg prior to randomization
  4. Documented allergy or adverse reaction to milrinone

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02077010


Contacts
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Contact: Zachary L Cox, PharmD 901-201-1683 zachary.l.cox@vanderbilt.edu
Contact: Nicholas Haglund, MD 207-332-2933 nhaglund@kumc.edu

Locations
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United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37204
Contact: Zachary L Cox, PharmD    901-201-1683    zachary.l.cox@vanderbilt.edu   
Principal Investigator: Nicholas Haglund, MD         
Principal Investigator: Zachary L Cox, PharmD         
Sponsors and Collaborators
Vanderbilt University Medical Center
University of Kansas
Investigators
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Principal Investigator: Nicholas Haglund, MD University of Kansas
Principal Investigator: Zachary L Cox, PharmD Vanderbilt University Medical Center/ Lipscomb University College of Pharmacy

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Responsible Party: Zachary L. Cox, Clinical Pharmacist, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT02077010     History of Changes
Other Study ID Numbers: 170530
First Posted: March 4, 2014    Key Record Dates
Last Update Posted: January 11, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Zachary L. Cox, Vanderbilt University Medical Center:
milrinone
heart failure
cardiomyopathy
inhaled

Additional relevant MeSH terms:
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Heart Failure
Cardiomyopathies
Heart Diseases
Cardiovascular Diseases
Milrinone
Cardiotonic Agents
Platelet Aggregation Inhibitors
Vasodilator Agents
Phosphodiesterase 3 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs