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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
  Purpose
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).

Condition Intervention
Persistent Fetal Circulation Syndrome
Drug: Milrinone Lactate

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Milrinone Pharmacokinetics and Pharmacodynamics in Newborns With Persistent Pulmonary Hypertension of the Newborn - a Pilot Study to Enable a Randomized Trial of Intervention

Resource links provided by NLM:


Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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)


Enrollment: 12
Study Start Date: June 2010
Study Completion Date: May 2015
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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: 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.
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   up to 10 Days   (Child)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01088997

Locations
United States, Michigan
Children's Hospital of Michigan/Hutzel Women's Hospital
Detroit, Michigan, United States, 48201-2196
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Children's Hospital of Philadelphia
University of Pennsylvania
Bedford Pharmaceuticals
American Medical Association
Thrasher Research Fund
Investigators
Principal Investigator: Haresh Kirpalani, MD Children's Hospital of Philadelphia
  More Information

Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT01088997     History of Changes
Other Study ID Numbers: 09-007384 
Study First Received: March 12, 2010
Results First Received: May 20, 2015
Last Updated: June 2, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Children's Hospital of Philadelphia:
Persistent pulmonary hypertension of newborn
PPHN
Persistent pulmonary hypertension
Pulmonary hypertension
Pulmonary hypertension of newborn

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Persistent Fetal Circulation Syndrome
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Infant, Newborn, 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

ClinicalTrials.gov processed this record on September 26, 2016