Trial Outcomes & Findings for Pharmacokinetic Study of Milrinone in Babies With Persistent Pulmonary Hypertension of the Newborn (NCT NCT01088997)

Last Updated: 2016-07-12

Results Overview

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.

Recruitment status

TERMINATED

Study phase

Target enrollment

12 participants

Primary outcome timeframe

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)

Results posted on

2016-07-12

Participant Flow

Recruitment began in June 2010 at three large academic medical centers. The study was closed to enrollment at all sites in November 2013.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	7	5
Overall Study COMPLETED	4	2
Overall Study NOT COMPLETED	3	3

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Physician Decision	1	1
Overall Study Req. Extracorporeal membrane oxygenation	1	1
Overall Study Excluded prior to receiving drug	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	High Dose Milrinone n=7 Participants 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	Low Dose Milrinone n=5 Participants 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	Total n=12 Participants Total of all reporting groups
Age, Categorical <=18 years	7 Participants n=5 Participants	5 Participants n=7 Participants	12 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	1 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment United States	7 participants n=5 Participants	5 participants n=7 Participants	12 participants n=5 Participants

PRIMARY outcome

Timeframe: 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)

Population: 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.

Outcome measures

Outcome measures
Measure	High Dose Milrinone n=6 Participants 7 subjects were enrolled into this arm, of these only 4 completed study treatment.	Low Dose Milrinone 5 subjects were enrolled into this arm, of these only 2 completed study treatment.
Define Plasma Concentration-time Profile of Milrinone in Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) - Clearance (CL, mL/Min)	7.65 mL/min/3.4 kg Standard Error 18.8	—

SECONDARY outcome

Timeframe: for up to 24 hours after start of infusion

Population: OI was calculated every 6 hours after start of infusion for 24 hours.

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.

Outcome measures

Outcome measures
Measure	High Dose Milrinone n=4 Participants 7 subjects were enrolled into this arm, of these only 4 completed study treatment.	Low Dose Milrinone n=2 Participants 5 subjects were enrolled into this arm, of these only 2 completed study treatment.
Change in Oxygenation Index (OI) From Baseline to up to 24 Hours After Start of Milrinone Infusion	4.9 units on a scale Standard Deviation 11.5	36.5 units on a scale Standard Deviation 27.0

SECONDARY outcome

Timeframe: Up to 24 hours after start of 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)

Outcome measures

Outcome measures
Measure	High Dose Milrinone n=4 Participants 7 subjects were enrolled into this arm, of these only 4 completed study treatment.	Low Dose Milrinone n=1 Participants 5 subjects were enrolled into this arm, of these only 2 completed study treatment.
Change in Myocardial Performance Index (MPI) From Baseline to up to 24 Hours After Start of Milrinone Infusion	-.12 units on a scale Standard Deviation 0.29	-.09 units on a scale Standard Deviation 0

Adverse Events

High Dose Milrinone

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Low Dose Milrinone

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	High Dose Milrinone n=7 participants at risk 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.	Low Dose Milrinone n=5 participants at risk 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.
Respiratory, thoracic and mediastinal disorders Hypoxia requiring ECMO	14.3% 1/7 • 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).	20.0% 1/5 • 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).
Renal and urinary disorders Renal insufficiency	0.00% 0/7 • 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).	20.0% 1/5 • 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).
Metabolism and nutrition disorders Hyperglycemia	28.6% 2/7 • 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).	0.00% 0/5 • 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).
Renal and urinary disorders Hyponatremia	0.00% 0/7 • 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).	20.0% 1/5 • 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).
Hepatobiliary disorders Elevated Liver Function Tests	14.3% 1/7 • 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).	0.00% 0/5 • 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).

Additional Information

Haresh Kirpalani, MD, MSc

Children's Hospital of Philadelphia

Phone: 215-590-2455

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place