Clinical trial NCT02077010: Nebulized Inhaled Milrinone in a Hospitalized Advanced Heart Failure Population
Official title: Nebulized Inhaled Milrinone in a Hospitalized Advanced Heart Failure Population
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Heart Failure
Cardiomyopathy
Keywords: milrinone
heart failure
cardiomyopathy
inhaled
Lead sponsor: University of Kansas Medical Center
Sponsor class: OTHER
Collaborators: name: Vanderbilt University Medical Center
First posted: 2014-03-04
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

By doing this study the investigators hope to learn if a new way of giving HF patients milrinone can lower the levels of plasma milrinone which may lessen the chance of medication side effects, while still preserving the beneficial effects of milrinone. Additionally if the inhaled route of administration is effective patients may not need to have invasive IV lines to administer the medication (currently standard practice) which can cause other unwanted side effects.

Detailed description: Approximately 5.7 million Americans have heart failure, a leading cause of both morbidity and mortality in the United States. Heart failure was listed as a contributing cause in more than 280,000 deaths in 2008 in the U.S. (1 in 9) and about half of patients diagnosed with heart failure die within 5 years. Patients with end stage heart failure have significant symptoms (including fatigue and dyspnea) which prevent them from being able to perform most activities of daily living. These patients often require repeated or prolonged hospitalizations for disease management which contributes significantly to the cost of heart failure for the United States (34.4 billion each year).

Milrinone, a phosphodiesterase III inhibitor, is one of the inotropic medications that has been studied and used in the treatment of acutely decompensated heart failure. Several studies have evaluated chronic intravenous (IV) inotrope use in end stage heart failure for palliation of symptoms as well as evaluated effect on cost through decreased hospital readmissions. Hauptman et al and Harjai et al demonstrated significant decreases in hospital costs due to reductions in days hospitalized and readmissions after initiation of inotropes including milrinone. However, the concern with IV milrinone use is the possibility of increased mortality associated with therapy despite improved hemodynamics (increased cardiac output, decreased filling pressures) and symptoms as was observed with chronic use of oral inotropes. The OPTIME-CHF study confirmed this concern regarding the use of IV milrinone by reporting increased mortality in patients with New York Heart Association (NYHA) class III-IV ischemic heart failure without hemodynamic compromise as well as statistically significant increases in atrial and ventricular arrhythmias when using intravenous milrinone. For this reason, the American Heart Association/American College of Cardiology practice guidelines, recommend use of IV milrinone only for patients presenting with clinical evidence of hypotension associated with hypo-perfusion and elevated cardiac filling pressures in order to maintain systemic perfusion and preserve end-organ performance. Administration of chronic IV inotropes in heart failure patients with refractory symptoms is categorized as a class IIb indication ("usefulness/efficacy is less well established by expert opinion").

This is a prospective, non-blinded, open-label, phase I clinical trial. We plan to enroll a total of ten patients in two blocks of five. Enrollment will be stopped after the first block of 5 patients to analyze the pharmacokinetics and safety of inhaled milrinone. Patients will have advanced, end-stage HF - and at the discretion of their treating cardiologist who ordered the initial right heart catheterization (RHC) for evaluation of HF therapy, patients will be sent for right heart catheterization (RHC) to determine if inotropic therapy would be beneficial. If the treating cardiologist decides to initiate inotropic therapy based on current guideline-recommended therapies after RHC is performed, the patient will be considered for the trial as long as they meet all inclusion/exclusion criteria.

The investigators goals are two fold:

1. To demonstrate safety by monitoring for pre-specified adverse clinical events and by conducting patient reported questionnaires at 24 and 48 +/- 12 hours.
2. To characterize inhaled milrinone pharmacokinetics. Six plasma samples will be drawn at pre-specified time intervals related to inhaled milrinone delivery.

Eligibility 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

Primary outcomes:
measure: Safety Analysis
timeFrame: A patient questionnaire to ascertain patient reported adverse events will be peformed at 24 hours
measure: Pharmacokinetic analysis
timeFrame: Plasma samples will be drawn around the 4th inhaled dose and after the dose at the following time point of 0.5 hours to assess for serum milirinone concentration fro the trough to be no less than 50ng/ml and the peak to be no greater than 500ng/ml.
measure: Safety Analysis
timeFrame: A patient questionnaire to ascertain patient reported adverse events will be peformed at 48+/- 12 hours.
measure: Pharmacokinetic analysis
timeFrame: Plasma samples will be drawn around the 4th inhaled dose and after the dose at the following time point of 1 hour to assess for serum milirinone concentration fro the trough to be no less than 50ng/ml and the peak to be no greater than 500ng/ml.
measure: Pharmacokinetic analysis
timeFrame: Plasma samples will be drawn around the 4th inhaled dose and after the dose at the following time point of 2 hours to assess for serum milirinone concentration fro the trough to be no less than 50ng/ml and the peak to be no greater than 500ng/ml.
measure: Pharmacokinetic analysis
timeFrame: Plasma samples will be drawn around the 4th inhaled dose and after the dose at the following time point of 4 hours to assess for serum milirinone concentration fro the trough to be no less than 50ng/ml and the peak to be no greater than 500ng/ml.
measure: Pharmacokinetic analysis
timeFrame: Plasma samples will be drawn around the 4th inhaled dose and after the dose at the following time point of 8 hours to assess for serum milirinone concentration fro the trough to be no less than 50ng/ml and the peak to be no greater than 500ng/ml.
Secondary outcomes:
measure: All cause mortality
timeFrame: From date of randomization until study drug is completed (less than or equal to 72 hr after randomization)
Other outcomes:
measure: Study Withdrawal Criteria -1
timeFrame: From date of randomization until study drug is completed (less than or equal to 60 hr after randomization)
measure: Withdrawal criteria - 2
timeFrame: From date of randomization until study drug is completed (less than or equal to 60 hr after randomization)
measure: Withdrawal criteria - 3
timeFrame: From date of randomization until study drug is completed (less than or equal to 60 hr after randomization)
measure: Withdrawal criteria -4
timeFrame: From date of randomization until study drug is completed (less than or equal to 60 hr after randomization)
measure: Withdrawal criteria -5
timeFrame: From date of randomization until study drug is completed (less than or equal to 60 hr after randomization)
measure: Withdrawal criteria -6
timeFrame: From date of randomization until study drug is completed (less than or equal to 60 hr after randomization)
measure: Withdrawal criteria -7
timeFrame: From date of randomization until study drug is completed (less than or equal to 60 hr after randomization)
Locations:
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: University of Kansas
name: Zubair Shah, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University Medical Center/ Lipscomb University College of Pharmacy
name: Zachary L Cox, PharmD
role: PRINCIPAL_INVESTIGATOR
References: