Heart FailurePhase 1iMilrinoneNCT02077010
Nebulized Inhaled Milrinone in a Hospitalized Advanced Heart Failure Population
A Phase 1 study testing Inhaled nebulized milrinone in people with Heart Failure and Cardiomyopathy, run by University of Kansas Medical Center at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure, Cardiomyopathy
- What is being tested?
- Inhaled nebulized milrinone
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 2 sitesUnited States
- Study dates
- 15 Jun 2020to 24 Jan 2023
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients age > 18 years old
- Symptomatic Stage D heart failure requiring initiation of inotropic medication at the discretion of their cardiologist
- Signed informed consent
Who cannot join
- Patients incapable of signing informed consent for any reason
- Patients who are pregnant or breastfeeding
- Systolic blood pressure less than 85 mmHg prior to randomization
- Documented allergy or adverse reaction to milrinone
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of Kansas Medical Center
Kansas City, Kansas, 66160
Vanderbilt University Medical Center
Nashville, Tennessee, 37204
About this study
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.
Read the 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:
- To demonstrate safety by monitoring for pre-specified adverse clinical events and by conducting patient reported questionnaires at 24 and 48 +/- 12 hours.
- To characterize inhaled milrinone pharmacokinetics. Six plasma samples will be drawn at pre-specified time intervals related to inhaled milrinone delivery.
- Conditions
- Heart Failure, Cardiomyopathy
- Being tested
- Inhaled nebulized milrinone
- Keywords
- milrinone, heart failure, cardiomyopathy, inhaled
- Medical subject headings
- Heart Failure, Cardiomyopathies, Respiratory Aspiration
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Inhaled nebulized milrinoneDrug
inhaled nebulized milrinone 60mg/4ml
| Study group | Role | What they receive |
|---|---|---|
| Inhaled nebulized milrinone | Experimental | Inhaled nebulized milrinone 60mg/4ml every 8 hours using a jet nebulizer Receives: Drug: Inhaled nebulized milrinone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety Analysis
Safety analysis will consist of collecting patient reported adverse events around potential local (respiratory tree) adverse events resulting from the inhalation route and systemic adverse effects resulting from the effects of milrinone itself including ventricular tachycardia (VT), atrial arrhythmias, hypotension, and worsening hypoxia.
Measured: A patient questionnaire to ascertain patient reported adverse events will be peformed at 24 hours
Pharmacokinetic analysis
Patient will have serial plasma samples drawn to determine inhaled milrinone pharmacokinetics. A total of six 0.5ml plasma samples will be obtained.
Measured: 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.
Safety Analysis
Safety analysis will consist of collecting patient reported adverse events
Measured: A patient questionnaire to ascertain patient reported adverse events will be peformed at 48+/- 12 hours.
Pharmacokinetic analysis
Patient will have serial plasma samples drawn to determine inhaled milrinone pharmacokinetics. A total of six 0.5ml plasma samples will be obtained.
Measured: 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.
Pharmacokinetic analysis
Patient will have serial plasma samples drawn to determine inhaled milrinone pharmacokinetics. A total of six 0.5ml plasma samples will be obtained.
Measured: 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.
Pharmacokinetic analysis
Patient will have serial plasma samples drawn to determine inhaled milrinone pharmacokinetics. A total of six 0.5ml plasma samples will be obtained.
Measured: 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.
Pharmacokinetic analysis
Patient will have serial plasma samples drawn to determine inhaled milrinone pharmacokinetics. A total of six 0.5ml plasma samples will be obtained.
Measured: 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 (1)
All cause mortality
Death from any cause during the study period
Measured: From date of randomization until study drug is completed (less than or equal to 72 hr after randomization)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Mar 2014 (estimated)
- Study start15 Jun 2020
- Primary completion24 Jan 2023
- Study completion24 Jan 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by University of Kansas Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Kansas Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Vanderbilt University Medical Center
- Responsible party
- Sponsor
- Investigators
- Zubair Shah, MD, Principal investigator, University of KansasZachary L Cox, PharmD, Principal investigator, Vanderbilt University Medical Center/ Lipscomb University College of Pharmacy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02077010
- Sponsor's protocol ID
- 170530
- Acronym
- iMilrinone
- Status last verified
- Sep 2024
- First submitted
- 25 Feb 2014
- Last updated
- 19 Sep 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Cox ZL, Dalia T, Goyal A, Fritzlen J, Gupta B, Shah Z, Sauer AJ, Haglund NA. Novel Nebulized Milrinone Formulation for the Treatment of Acute Heart Failure Requiring Inotropic Therapy: A Phase 1 Study. J Card Fail. 2024 Feb;30(2):329-336. doi: 10.1016/j.cardfail.2023.08.025. Epub 2023 Oct 21.
PubMed 37871843
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Nebulized Inhaled Milrinone in a Hospitalized Advanced Heart Failure Population
- ClinicalTrials.gov ID
- NCT02077010
- Acronym / sponsor ID
- iMilrinone / 170530
- Conditions
- Heart Failure, Cardiomyopathy
- Keywords
- milrinone, heart failure, cardiomyopathy, inhaled
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- University of Kansas Medical CenterUniversity, hospital or other
- Collaborators
- Vanderbilt University Medical Center
- Study start
- 15 Jun 2020 (actual)
- Primary completion
- 24 Jan 2023 (actual)
- Study completion
- 24 Jan 2023 (actual)
- First posted
- 4 Mar 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- To demonstrate safety by monitoring for pre-specified adverse clinical events and by conducting patient reported questionnaires at 24 and 48 +/- 12 hours.
- To characterize inhaled milrinone pharmacokinetics. Six plasma samples will be drawn at pre-specified time intervals related to inhaled milrinone delivery.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Inhaled nebulized milrinone | Experimental | Drug: Inhaled nebulized milrinoneInhaled nebulized milrinone 60mg/4ml every 8 hours using a jet nebulizer |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Patients age > 18 years old
- Symptomatic Stage D heart failure requiring initiation of inotropic medication at the discretion of their cardiologist
- Signed informed consent
Key exclusion criteria (4 listed)
- Patients incapable of signing informed consent for any reason
- Patients who are pregnant or breastfeeding
- Systolic blood pressure less than 85 mmHg prior to randomization
- Documented allergy or adverse reaction to milrinone
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Inhaled nebulized milrinoneinhaled nebulized milrinone 60mg/4ml | Drug | Inhaled nebulized milrinone |
Primary outcome
Safety Analysis
Time frame: A patient questionnaire to ascertain patient reported adverse events will be peformed at 24 hours
Safety analysis will consist of collecting patient reported adverse events around potential local (respiratory tree) adverse events resulting from the inhalation route and systemic adverse effects resulting from the effects of milrinone itself including ventricular tachycardia (VT), atrial arrhythmias, hypotension, and worsening hypoxia.
Pharmacokinetic analysis
Time frame: 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.
Patient will have serial plasma samples drawn to determine inhaled milrinone pharmacokinetics. A total of six 0.5ml plasma samples will be obtained.
Safety Analysis
Time frame: A patient questionnaire to ascertain patient reported adverse events will be peformed at 48+/- 12 hours.
Safety analysis will consist of collecting patient reported adverse events
Pharmacokinetic analysis
Time frame: 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.
Patient will have serial plasma samples drawn to determine inhaled milrinone pharmacokinetics. A total of six 0.5ml plasma samples will be obtained.
Pharmacokinetic analysis
Time frame: 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.
Patient will have serial plasma samples drawn to determine inhaled milrinone pharmacokinetics. A total of six 0.5ml plasma samples will be obtained.
Pharmacokinetic analysis
Time frame: 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.
Patient will have serial plasma samples drawn to determine inhaled milrinone pharmacokinetics. A total of six 0.5ml plasma samples will be obtained.
Pharmacokinetic analysis
Time frame: 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.
Patient will have serial plasma samples drawn to determine inhaled milrinone pharmacokinetics. A total of six 0.5ml plasma samples will be obtained.
1 secondary outcome
All cause mortality
Time frame: From date of randomization until study drug is completed (less than or equal to 72 hr after randomization)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2024.
- Derived from this study: PubMed 37871843Cox ZL, Dalia T, Goyal A, Fritzlen J, Gupta B, Shah Z, Sauer AJ, Haglund NA. Novel Nebulized Milrinone Formulation for the Treatment of Acute Heart Failure Requiring Inotropic Therapy: A Phase 1 Study. J Card Fail. 2024 Feb;30(2):329-336. doi: 10.1016/j.cardfail.2023.08.025. Epub 2023 Oct 21.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Zubair Shah, MD principal investigator
University of Kansas
Zachary L Cox, PharmD principal investigator
Vanderbilt University Medical Center/ Lipscomb University College of Pharmacy
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Inhaled nebulized milrinone in people with Heart Failure and Cardiomyopathy, run by University of Kansas Medical Center at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety Analysis (time frame: A patient questionnaire to ascertain patient reported adverse events will be peformed at 24 hours). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02077010, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2024.