Clinical trial NCT06679855: Milrinone for Prevention of Post-ligation Cardiac Syndrome Trial
Official title: Milrinone for Prevention of Post-ligation Cardiac Syndrome Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Post-ligation Cardiac Syndrome
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2024-11-08
Enrollment: 316
Sex: ALL
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The goal of this Phase 3, randomized, masked clinical trial is to is to find out whether milrinone, when given to infants after PDA closure, will help the heart work better by supplying oxygen to the lungs and tissues.

The main questions it aims to answer are:

1. to determine if milrinone decreases the risk of death or PLCS within 7 days of the procedure, compared to standard treatment; and
2. to determine the effects of milrinone on two-year survival and neurodevelopmental outcome.

Detailed description: Researchers will compare milrinone to a placebo saline solution to see if it helps the heart work better by supplying oxygen to the lungs and tissues.

After randomization the following will happen in both the control and treatment groups:

* Infant will start receiving either a low dose (0.33 μg/kg/min) of milrinone in the treatment group, OR saline solution in the control group through an intravenous (IV) line. The study drug will be started within 2 hours of the PDA closure procedure.
* For the first 2 to 4 hours, the study team will monitor very closely to see if there are any major side effects from the study drug.
* If the infant continues to have high blood pressure, which places an added stress on the heart, the dose will go up to 0.66 μg/kg/min. One more increase will be allowed to 0.75 μg/kg/min. The study drug will then stay at this dose. No more changes will happen to the dose. If there are side effects, then the study drug will be stopped and will not be started again.
* The study drug will be stopped after 24 hours if the infant only required the lowest drug and remains well. If the required higher doses of milrinone, it will take longer to wean them off the medication. Some infants may receive milrinone for 3-5 days. If the infant's heart starts to work better by using less oxygen from the breathing machine (ventilator), the study drug may be stopped before 3 days.
* Information will be collected from the infant's medical record including demographic information, gestational age, blood pressures, heart rates, respiratory rates, information about his or her breathing, medications, details of medical treatment for PDA, medical procedures including echocardiograms (ultrasound of the baby's heart), details of PDA closure (by surgery or transcatheter closure), head ultrasounds, and diagnoses. The investigators will also be collecting information from the maternal medical record including ultrasounds that may be relevant to the infant's course.
* Right after the study drug is stopped (which could be 5 days or less) the doctor may decide to give the infant the drug milrinone. This is a decision that will be made by the infant's doctor.
* After the infant goes home from the hospital, they will be scheduled for follow-up exams in the clinic. The follow-up visit will be done when the infant is about 2 years old. The visit will take about two hours to do. During the follow-up visit the investigators will test the infant's movement, behavior, and development. The investigators will also check the infant to make sure they do not have high blood pressure or any evidence of kidney disease.

Eligibility criteria: Inclusion Criteria:

* Gestational age at birth ≤27 weeks (and 6 days) and postnatal age \< 3 months at intervention
* Invasive or non-invasive positive pressure respiratory support (does not include low flow nasal cannula)
* Hemodynamically significant PDA with minimum transductal diameter ≥1.0 mm within 2 days of intervention
* Decision by clinical team to proceed with PDA closure via surgical ligation or percutaneous cardiac catheterization based on clinical and echocardiography features of hemodynamic significance.

Exclusion Criteria:

* Any major congenital malformation
* Congenital heart disease (except small (≤1mm) muscular ventricular septal defects, or small/moderate (\<3mm) atrial septal defect)
* Acute renal failure defined by urine output \< 0.5 mL/kg/hour OR rise of serum creatinine by 0.3 mg/dL within 48 hours OR rise of serum creatinine more than 40% above baseline serum creatinine within prior 72 hours.
* Systemic administration of vasodilator/inodilator agents
* Prior history of arrhythmia

Primary outcomes:
measure: Post-ligation cardiac syndrome (PLCS) or death within 7 days of PDA closure
timeFrame: Onset within 48 hours but may last up to 7 days
Secondary outcomes:
measure: Systemic hypotension
timeFrame: Onset within 48 hours but may last up to 7 days
measure: Systemic hypertension
timeFrame: Onset within 48 hours but may last up to 7 days
measure: Oxygenation failure
timeFrame: Onset within 48 hours but may last up to 7 days
measure: Ventilation failure
timeFrame: Within 72 hours of PDA closure
measure: Vasopressor score
timeFrame: Within 7 days of PDA closure
measure: Use of open-label milrinone or systemic vasodilator after cessation of study drug administration
timeFrame: After study drug cessation and within 7 days of PDA closure
measure: Time to successful extubation
timeFrame: 36 weeks postmenstrual age
measure: Post-intervention Moderate-severe bronchopulmonary dysplasia at 36 weeks' gestation
timeFrame: 36 weeks postmenstrual age
measure: Post-intervention Chronic Pulmonary hypertension
timeFrame: 36 weeks postmenstrual age
measure: Post-intervention Periventricular Leukomalacia (PVL)
timeFrame: 36 weeks postmenstrual age
measure: Post-intervention Necrotizing Enterocolitis
timeFrame: 36 weeks postmenstrual age
measure: Post-intervention Retinopathy of Prematurity (ROP) ≥ stage 3 (according to the international classification)
timeFrame: 36 weeks postmenstrual age
measure: Weight or head circumference z-score change at 36 weeks
timeFrame: 36 weeks postmenstrual age
measure: Death between randomization and discharge from NICU
timeFrame: Randomization to 120 days' postnatal age, death, discharge, or transfer outside of the Study Center, whichever occurs first (an average of 112 days postnatal age)
measure: Moderate-Severe neurodevelopmental impairment (NDI), using current NRN Follow-Up Study definition
timeFrame: 22 to 26 months
measure: Moderate-Severe neurodevelopmental impairment (NDI) or death
timeFrame: 22 to 26 months
measure: Moderate or severe cerebral palsy
timeFrame: 22 to 26 months
measure: Severe vision impairment
timeFrame: 22 to 26 months
measure: Severe hearing impairment
timeFrame: 22 to 26 months
measure: Bayley-4 cognitive, language, motor scores
timeFrame: 22 to 26 months
measure: Gross Motor Function level ≥II
timeFrame: 22 to 26 months
measure: CBCL Internalizing, Externalizing, and Total Problems aggregate T scores of >64 (clinical range) and 60-63 (borderline range).
timeFrame: 22 to 26 months
measure: Death before 22-26-month follow-up
timeFrame: 22 to 26 months
measure: Height, weight, or head circumference growth failure
timeFrame: 22 to 26 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Diego
country: United States
facility: Sharp Mary Birch Hospital for Women & Newborns
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern Lurie Children's Hospital of Chicago
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Memphis
country: United States
facility: Le Bonheur Children's Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Houston
country: United States
facility: University of Texas at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
References: