Pharmacokinetic Study of Milrinone in Babies With Persistent Pulmonary Hypertension of the Newborn

This study has been terminated.
(Inadequate enrollment)
Sponsor:
Collaborators:
University of Pennsylvania
Bedford Pharmaceuticals
American Medical Association
Thrasher Research Fund
Information provided by (Responsible Party):
Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:
NCT01088997
First received: March 12, 2010
Last updated: June 2, 2016
Last verified: June 2016

March 12, 2010
June 2, 2016
June 2010
February 2013   (final data collection date for primary outcome measure)
Define Plasma Concentration-time Profile of Milrinone in Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) - Clearance (CL, mL/Min) [ Time Frame: 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) ] [ Designated as safety issue: No ]
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.
Pharmacokinetic profile of milrinone in newborns with PPHN [ Time Frame: according to weight (see below) ] [ Designated as safety issue: No ]
For infants <3 kg, samples will be collected at end of bolus, 15min prior to end of infusion (EOI), and after EOI at 20min, 1hr, 2hr, 6hr, & 12 hr. For infants >3 kg, samples will be collected at end of bolus, 6 hours after start of infusion, 15min prior to end of infusion (EOI), and after EOI at 30min, 1hr, 3hr, 9hr, & 15 hr. Samples will be stored at -70C and milrinone plasma concentrations measured by modification of a high-pressure liquid chromatography assay in laboratory of Clinical Pharmacology and Therapeutics at CHOP.
Complete list of historical versions of study NCT01088997 on ClinicalTrials.gov Archive Site
  • Change in Oxygenation Index (OI) From Baseline to up to 24 Hours After Start of Milrinone Infusion [ Time Frame: for up to 24 hours after start of infusion ] [ Designated as safety issue: No ]
    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.
  • Change in Myocardial Performance Index (MPI) From Baseline to up to 24 Hours After Start of Milrinone Infusion [ Time Frame: Up to 24 hours after start of infusion ] [ Designated as safety issue: No ]
    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)
  • Oxygenation index [ Time Frame: every 6 hours for 48 hours ] [ Designated as safety issue: No ]
    Oxygenation index (mean airway pressure*FiO2/PaO2) will be calculated every 6 hours.
  • Echocardiographic signs of pulmonary hypertension [ Time Frame: 12-24 hours ] [ Designated as safety issue: No ]
    An echocardiogram obtained while on milrinone will look for improvements in parameters associated with pulmonary hypertension. Parameters measured will be: myocardial performance index (MPI) of LV and RV, cardiac output of LV, tricuspid regurgitation (trivial, mild, moderate, severe), RV systolic pressure, mitral regurgitation (trivial, mild, moderate, severe), presence or absence of patent foramen ovale (PFO) with peak and mean pressure gradient, and presence or absence of patent ductus arteriosus (PDA) with peak and mean pressure gradient.
  • Safety profile [ Time Frame: 24-48 hours ] [ Designated as safety issue: Yes ]
    Safety analysis will be performed as follows: blood pressure will be monitored hourly for 48 hours, platelet count will be measured daily, cardiac rhythm will be monitored continuously for 48 hours, renal function will be monitored daily, and liver transaminases will be monitored within a week. All adverse events will be included in the safety analysis. Interim safety analyses will be performed after 1/3 and 2/3 of subjects have been enrolled. A data safety monitoring committee will meet monthly to discuss adverse events and interim analyses.
Not Provided
Not Provided
 
Pharmacokinetic Study of Milrinone in Babies With Persistent Pulmonary Hypertension of the Newborn
Milrinone Pharmacokinetics and Pharmacodynamics in Newborns With Persistent Pulmonary Hypertension of the Newborn - a Pilot Study to Enable a Randomized Trial of Intervention
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.

Interventional
Not Provided
Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Persistent Fetal Circulation Syndrome
Drug: Milrinone Lactate
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.
Other Name: Milrinone
  • Experimental: High Dose Milrinone
    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.
    Intervention: Drug: Milrinone Lactate
  • Experimental: Low Dose Milrinone
    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.
    Intervention: Drug: Milrinone Lactate
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
12
May 2015
February 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Gestational age > 34 weeks
  • Post-natal age < 10 days
  • Hypoxemia defined by: Oxygenation Index (OI) >15 (Mean Airway Pressure x Fraction of Inspired Oxygen (FiO2) x 100 /PaO2) as drawn from two post-ductal arterial blood gas samples (in-dwelling arterial catheter) taken at least 15 minutes apart. OR mechanically ventilated and with >75% FiO2 for >6 hours while on iNO
  • Absence of congenital heart disease based on a two-dimensional echocardiogram and/or clinical assessment
  • An in-dwelling arterial catheter to facilitate painless sampling
  • Currently on iNO or plan to start iNO before enrollment

Exclusion Criteria:

  • Lethal non-cardiac congenital anomalies including diaphragmatic hernia
  • Clinically apparent bleeding; thrombocytopenia <30,000 or other laboratory evidence of coagulopathy
  • Currently on extracorporeal membrane oxygenation (ECMO)or plan to initiate ECMO within 2 hours of enrollment
Both
up to 10 Days   (Child)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01088997
09-007384
Yes
Not Provided
Not Provided
Children's Hospital of Philadelphia
Children's Hospital of Philadelphia
  • University of Pennsylvania
  • Bedford Pharmaceuticals
  • American Medical Association
  • Thrasher Research Fund
Principal Investigator: Haresh Kirpalani, MD Children's Hospital of Philadelphia
Children's Hospital of Philadelphia
June 2016

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