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Inadequate enrollment
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| Name | Class |
|---|---|
| University of Pennsylvania | OTHER |
| Bedford Pharmaceuticals | INDUSTRY |
| American Medical Association | OTHER |
| Thrasher Research Fund |
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The purpose of this pilot study is to determine a safe dose of milrinone to use in a larger study of babies with persistent pulmonary hypertension of the newborn (PPHN).
Persistent pulmonary hypertension of the newborn (PPHN) is a condition in which the pulmonary vasculature fails to relax after birth resulting in severe hypoxemia. This condition has a high rate of mortality and morbidity. The current standard of care is treatment with inhaled nitric oxide (iNO). However, for many babies this treatment does not provide sufficient improvement in oxygenation.
In this study, subjects already receiving nitric oxide will be randomized to one of two dosing regimens of milrinone. They will receive milrinone IV for 24 hours and will be monitored for 24 hours afterwards. During this time, milrinone assays will be performed by blood sampling. Echocardiograms will also be performed to explore the pharmacodynamics of milrinone. Safety monitoring will be performed.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| High Dose Milrinone | Experimental | Subjects will receive a bolus intravenous (IV) infusion of 50 mcg/kg/min of milrinone lactate over 1 hour followed by a continuous IV infusion of 0.5 mcg/kg/min milrinone lactate over 24 hours. After completion of infusion, subjects will be monitored for an additional 24 hours. |
|
| Low Dose Milrinone | Experimental | Subjects will receive a bolus intravenous (IV) infusion of 20 mcg/kg/min of milrinone lactate over 1 hour followed by a continuous IV infusion of 0.2 mcg/kg/min milrinone lactate over 24 hours. After completion of infusion, subjects will be monitored for an additional 24 hours. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Milrinone Lactate | Drug | Milrinone lactate will be given first as an IV bolus over one hour at the assigned dose level, followed by a 24 hour IV infusion at the assigned dose level. |
| Measure | Description | Time Frame |
|---|---|---|
| Define Plasma Concentration-time Profile of Milrinone in Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) - Clearance (CL, mL/Min) | The schedule of milrinone pharmacokinetic (PK) sampling varied by weight to minimize blood sampling. For babies weighing less than 3kg, samples were drawn at the end of the bolus, 15 minutes prior to the end of infusion (EOI) and 20 minutes, 1, 2, 6 and 12 hours after EOI. For babies weighing 3kg or more, samples were drawn at the end of the bolus, 6 hours after start of infusion, 15 minutes prior to the EOI and 30 minutes, 1, 3, 9 and 15 hours after EOI. Milrinone plasma concentrations were determined using a validated high-performance mass spectrometry assay. | End of bolus dose, 15 minutes prior to end of infusion (EOI), at four time points after EOI with final sample at 12-15 hours after EOI (timing based on infant's weight) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Oxygenation Index (OI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | Oxygenation Index (mean airway pressure*Fraction of Inspired Oxygen/Partial Pressure of Oxygen in the blood) was calculated at baseline and every 6 hours after start of infusion until 12-24 hours after initiation of milrinone infusion. | for up to 24 hours after start of infusion |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Haresh Kirpalani, MD | Children's Hospital of Philadelphia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital of Michigan/Hutzel Women's Hospital | Detroit | Michigan | 48201-2196 | United States | ||
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Recruitment began in June 2010 at three large academic medical centers. The study was closed to enrollment at all sites in November 2013.
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| ID | Title | Description |
|---|---|---|
| FG000 | High Dose Milrinone | Subjects received a 50 mcg/kg loading dose of milrinone lactate given intravenously (IV) over 1 hour followed by an IV infusion of 0.5 mcg/kg/min over 24 hours. |
| FG001 | Low Dose Milrinone | Subjects received a 20 mcg/kg loading dose of milrinone lactate given intravenously (IV) over 1 hour followed by an IV infusion of 0.2 mcg/kg/min over 24 hours. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | High Dose Milrinone | Subjects received a 50mcg/kg loading dose of milrinone lactate given intravenously (IV) over 1 hour followed by an IV infusion of 0.5mcg/kg over 24 hours |
| BG001 | Low Dose Milrinone |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Secondary | Change in Oxygenation Index (OI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | Oxygenation Index (mean airway pressure*Fraction of Inspired Oxygen/Partial Pressure of Oxygen in the blood) was calculated at baseline and every 6 hours after start of infusion until 12-24 hours after initiation of milrinone infusion. | OI was calculated every 6 hours after start of infusion for 24 hours. | Posted | Mean | Standard Deviation | units on a scale | for up to 24 hours after start of infusion |
|
Adverse event assessment was performed continuously from baseline (pre-infusion) through 24 hours after the completion of the milrinone infusion (total of 48 hours).
Included vital signs (i.e., blood pressure, measured hourly per standard of care), cardiorespiratory monitoring (ii.e., cardiac rhythm monitored continuously per standard of care), laboratory data (arterial blood gas collected ever 4 hours; hematology and serum chemistry collected every 24 hours), and head ultrasound (pre/post infusion).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | High Dose Milrinone | Subjects received a bolus intravenous (IV) infusion of 50 mcg/kg/min of milrinone lactate over 1 hour followed by a continuous IV infusion of 0.5 mcg/kg/min milrinone lactate over 24 hours. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypoxia requiring ECMO | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
Study enrollment was terminated early resulting in a small number of evaluable subjects for analysis.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Haresh Kirpalani, MD, MSc | Children's Hospital of Philadelphia | 215-590-2455 | kirpalanih@email.chop.edu |
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| ID | Term |
|---|---|
| D010547 | Persistent Fetal Circulation Syndrome |
| D006976 | Hypertension, Pulmonary |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| ID | Term |
|---|---|
| D020105 | Milrinone |
| ID | Term |
|---|---|
| D000676 | Amrinone |
| D000631 | Aminopyridines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D011725 |
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| OTHER |
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|
| Change in Myocardial Performance Index (MPI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | An echocardiogram obtained while on milrinone was obtained with the goal of attempting to look for improvements in parameters associated with pulmonary hypertension. The primary parameter measured was the myocardial performance index (MPI). An Echocardiogram was performed at baseline (pre-infusion) and repeated 12-24 hours ater the initiation of the Milrinone infusion. Also known as the Tei index, the MPI is an index that incorporates both systolic and diastolic time intervals in expressing global systolic and diastolic ventricular function. Systolic dysfunction prolongs preejection (isovolumic contraction time, IVCT) and a shortening of the ejection time (ET). Both systolic and diastolic dysfunction result in abnormality in myocardial relaxation which prolongs the relaxation period (isovolumic relaxation time, IVRT). Normal value for MPI is 0.39+/-0.05 with dilated cardiomyopathy value of MPI at 0.59+/-0.10 (both units on a scale) | Up to 24 hours after start of infusion |
| The Children's Hospital of Philadelphia |
| Philadelphia |
| Pennsylvania |
| 19104 |
| United States |
| Excluded prior to receiving drug |
|
Subjects received a 20mcg/kg loading dose of milrinone lactate given intravenously (IV) over 1 hour followed by an IV infusion of 0.2mcg/kg over 24 hours
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
5 subjects were enrolled into this arm, of these only 2 completed study treatment.
|
|
| Primary | Define Plasma Concentration-time Profile of Milrinone in Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) - Clearance (CL, mL/Min) | The schedule of milrinone pharmacokinetic (PK) sampling varied by weight to minimize blood sampling. For babies weighing less than 3kg, samples were drawn at the end of the bolus, 15 minutes prior to the end of infusion (EOI) and 20 minutes, 1, 2, 6 and 12 hours after EOI. For babies weighing 3kg or more, samples were drawn at the end of the bolus, 6 hours after start of infusion, 15 minutes prior to the EOI and 30 minutes, 1, 3, 9 and 15 hours after EOI. Milrinone plasma concentrations were determined using a validated high-performance mass spectrometry assay. | The pharmacokinetic analysis, including the primary outcome parameter, Clearance, was planned a priori to include all the participants pooled together. A PK analysis by arm wouldn't be appropriate. The randomization arms were only created to explore the secondary clinical and pharmacodynamic outcomes. | Posted | Mean | Standard Error | mL/min/3.4 kg | End of bolus dose, 15 minutes prior to end of infusion (EOI), at four time points after EOI with final sample at 12-15 hours after EOI (timing based on infant's weight) |
|
|
|
| Secondary | Change in Myocardial Performance Index (MPI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | An echocardiogram obtained while on milrinone was obtained with the goal of attempting to look for improvements in parameters associated with pulmonary hypertension. The primary parameter measured was the myocardial performance index (MPI). An Echocardiogram was performed at baseline (pre-infusion) and repeated 12-24 hours ater the initiation of the Milrinone infusion. Also known as the Tei index, the MPI is an index that incorporates both systolic and diastolic time intervals in expressing global systolic and diastolic ventricular function. Systolic dysfunction prolongs preejection (isovolumic contraction time, IVCT) and a shortening of the ejection time (ET). Both systolic and diastolic dysfunction result in abnormality in myocardial relaxation which prolongs the relaxation period (isovolumic relaxation time, IVRT). Normal value for MPI is 0.39+/-0.05 with dilated cardiomyopathy value of MPI at 0.59+/-0.10 (both units on a scale) | Posted | Mean | Standard Deviation | units on a scale | Up to 24 hours after start of infusion |
|
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| 0 |
| 7 |
| 4 |
| 7 |
| EG001 | Low Dose Milrinone | Subjects received a bolus intravenous (IV) infusion of 20 mcg/kg/min of milrinone lactate over 1 hour followed by a continuous IV infusion of 0.2 mcg/kg/min milrinone lactate over 24 hours. | 0 | 5 | 3 | 5 |
| Renal insufficiency | Renal and urinary disorders | Systematic Assessment |
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| Hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hyponatremia | Renal and urinary disorders | Systematic Assessment |
|
| Elevated Liver Function Tests | Hepatobiliary disorders | Systematic Assessment |
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| D006973 | Hypertension |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |