Milrinone for Prevention of Post-ligation Cardiac Syndrome Trial (MIDAS)

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.

Study Overview

• Status: Recruiting
• Conditions: Post-ligation Cardiac Syndrome
• Intervention / Treatment: Drug: Placebo infusion; Drug: Milrinone infusion

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.

• Study Type: Interventional
• Enrollment (Estimated): 316
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Valerie Chock; Phone Number: 650-723-5711; Email: vchock@stanford.edu
• Study Contact Backup: Name: Patrick J McNamara; Phone Number: 319-467-7435; Email: patrick-mcnamara@uiowa.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • Not yet recruiting
      • University of Alabama - Birmingham
      • Contact: Waldemar A Carlo; Phone Number: 205-934-4680; Email: wcarlo@peds.uab.edu
  • California
    • Orange, California, United States, 92868
      • Not yet recruiting
      • Children's Hospital of Orange County
      • Contact: Amir H Ashrafi; Phone Number: 714-509-4373; Email: Aashrafi@choc.org
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford University
      • Contact: Valerie Chock; Phone Number: 650-723-5711; Email: vchock@stanford.edu
    • San Diego, California, United States, 92123
      • Not yet recruiting
      • Sharp Mary Birch Hospital for Women & Newborns
      • Contact: Anup Katheria; Phone Number: 858-939-4170; Email: anup.katheria@sharp.com
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University
      • Contact: Ravi M Patel; Phone Number: 404-727-5905; Email: rmpatel@emory.edu
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern Lurie Children's Hospital of Chicago
      • Contact: Aaron Hamvas; Phone Number: 312-227-4190; Email: ahamvas@luriechildrens.org
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa
      • Contact: Tarah Colaizy; Phone Number: 319-356-3508; Email: tarah-colaizy@uiowa.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: Philip Levy; Phone Number: 617-919-2358; Email: Philip.Levy@childrens.harvard.edu
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • Not yet recruiting
      • University of Mississippi Medical Center
      • Contact: Abhay Bhatt; Phone Number: 601-984-5263; Email: abhatt@umc.edu
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • Recruiting
      • University of New Mexico
      • Contact: Janell Fuller; Phone Number: 505-272-6409; Email: jafuller@salud.unm.edu
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Recruiting
      • Duke University
      • Contact: Michael Cotten; Phone Number: 919-681-0630; Email: michael.cotten@duke.edu
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Stephanie Merhar; Phone Number: 513-803-5180; Email: Stephanie.Merhar@cchmc.org
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Case Western Reserve University
      • Contact: Anna Maria Hibbs; Phone Number: 216-844-3387; Email: annamaria.hibbs@cwru.edu
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • University of Oklahoma Health Sciences
      • Contact: Marjorie Makoni; Phone Number: 405-271-5215; Email: Marjorie-Makoni@ouhsc.edu
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Contact: Sara DeMauro; Phone Number: 215-590-3730; Email: demauro@email.chop.edu
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • Recruiting
      • Le Bonheur Children's Hospital
      • Contact: Mark Weems; Phone Number: 901-448-2262; Email: mweems@uthsc.edu
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • University of Texas Southwestern
      • Contact: Myra H Wyckoff; Phone Number: 214-590-4003; Email: myra.wyckoff@utsouthwestern.edu
    • Houston, Texas, United States, 77030
      • Recruiting
      • University of Texas at Houston
      • Contact: Matthew Rysavy; Phone Number: 713-500-6643; Email: matthew.a.rysavy@uth.tmc.edu
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • Recruiting
      • University of Utah
      • Contact: Robin Ohls; Phone Number: 801-213-1487; Email: robin.ohls@hsc.utah.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; An iv infusion of placebo (0.9% saline) of equivalent volume will be administered. The infusion will be accompanied by an iv bolus of 10 mL/kg of 0.9% NaCl (administered over 60 minutes) to ensure blinding is maintained.	Drug: Placebo infusion; An iv infusion of placebo (0.9% saline) of equivalent volume will be administered. The infusion will be accompanied by an iv bolus of 10 mL/kg of 0.9% NaCl (administered over 60 minutes) to ensure blinding is maintained.
Active Comparator: Milrinone; An intravenous (iv) infusion of milrinone will be administered at an initial dose of 0.33 mcg/kg/min and accompanied by an iv bolus of 10 mL/kg of 0.9% NaCl (administered over 60 minutes).	Drug: Milrinone infusion; An intravenous (iv) infusion of milrinone will be administered at an initial dose of 0.33 mcg/kg/min and accompanied by an iv bolus of 10 mL/kg of 0.9% NaCl (administered over 60 minutes).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-ligation cardiac syndrome (PLCS) or death within 7 days of PDA closure	Composite outcome of post-ligation cardiac syndrome (PLCS) or death within 7 days of PDA closure. Onset within 48 hours but may last up to 7 days.	Onset within 48 hours but may last up to 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic hypotension	Either systolic blood pressure below the 3rd percentile for gestational age or mean blood pressure below the postmenstrual age equivalent	Onset within 48 hours but may last up to 7 days
Systemic hypertension	Systolic blood pressure above the 97th percentile	Onset within 48 hours but may last up to 7 days
Oxygenation failure	An absolute increase of at least 20% in the fraction of inspired oxygen or mean airway pressure compared with the one-hour post-intervention value that persists for a minimum of 1 hour and occurs within 72 hours of PDA closure	Onset within 48 hours but may last up to 7 days
Ventilation failure	Need for high frequency oscillatory ventilation when conventional ventilation strategies fail or a 20% rise in amplitude compared with the one-hour post-intervention value that persists for a minimum of 1 hour and occurs within 72 hours of PDA closure	Within 72 hours of PDA closure
Vasopressor score	Vasopressor score. Minimum score is zero. Higher score is worse, meaning need for higher level of support. VISmax will be calculated as follows: (VIS=dopamine dose [μg kg-1 min-1]+dobutamine [μg kg-1 min-1]+100×epinephrine dose [μg kg-1 min-1]+50×levosimendan dose [μg kg-1 min-1]+10×milrinone dose [μg kg-1 min-1]+10 000×vasopressin [units kg-1 min-1]+100×norepinephrine dose [μg kg-1 min-1]) using the maximum dosing rates of vasoactive and inotropic medications (μg kg-1 min-1 or IU kg-1 min-1)	Within 7 days of PDA closure
Use of open-label milrinone or systemic vasodilator after cessation of study drug administration	Number of participants using open-label milrinone or systemic vasodilator after cessation of study drug administration	After study drug cessation and within 7 days of PDA closure
Time to successful extubation	Time to successful extubation, which is defined as extubation for at least 7 days	36 weeks postmenstrual age
Post-intervention Moderate-severe bronchopulmonary dysplasia at 36 weeks' gestation	Need for at least 2 liters of high flow nasal cannula at 36 weeks postmenstrual age	36 weeks postmenstrual age
Post-intervention Chronic Pulmonary hypertension	presence of septal flattening (or eccentricity index > 1.3, right ventricular systolic pressure greater than 40 mmHg, or exclusive right to left atrial level shunt on 36-week echocardiography assessment. The presence of a large atrial septal defect, pulmonary vein stenosis or left ventricular diastolic dysfunction will be recorded.	36 weeks postmenstrual age
Post-intervention Periventricular Leukomalacia (PVL)	Presence of cystic white matter changes on cranial ultrasound	36 weeks postmenstrual age
Post-intervention Necrotizing Enterocolitis	At least Bells stage IIb disease	36 weeks postmenstrual age
Post-intervention Retinopathy of Prematurity (ROP) ≥ stage 3 (according to the international classification)	Post-intervention Retinopathy of Prematurity (ROP) ≥ stage 3 (according to the international classification)	36 weeks postmenstrual age
Weight or head circumference z-score change at 36 weeks	Weight or head circumference z-score change at 36 weeks (decline by two z-scores will be considered growth failure)	36 weeks postmenstrual age
Death between randomization and discharge from NICU	Death between randomization and discharge from NICU	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)
Moderate-Severe neurodevelopmental impairment (NDI), using current NRN Follow-Up Study definition	Moderate-Severe neurodevelopmental impairment (NDI), using current NRN Follow-Up Study definition	22 to 26 months
Moderate-Severe neurodevelopmental impairment (NDI) or death	Moderate-Severe neurodevelopmental impairment (NDI) or death	22 to 26 months
Moderate or severe cerebral palsy	Moderate or severe cerebral palsy	22 to 26 months
Severe vision impairment	Severe vision impairment	22 to 26 months
Severe hearing impairment	Severe hearing impairment	22 to 26 months
Bayley-4 cognitive, language, motor scores	Bayley-4 cognitive, language, motor scores	22 to 26 months
Gross Motor Function level ≥II	Gross Motor Function level ≥II	22 to 26 months
CBCL Internalizing, Externalizing, and Total Problems aggregate T scores of >64 (clinical range) and 60-63 (borderline range).	CBCL Internalizing, Externalizing, and Total Problems aggregate T scores of >64 (clinical range) and 60-63 (borderline range).	22 to 26 months
Death before 22-26-month follow-up	Death before 22-26-month follow-up	22 to 26 months
Height, weight, or head circumference growth failure	Height, weight, or head circumference growth failure (decline by >2 z-scores since discharge)	22 to 26 months

Collaborators and Investigators

• Sponsor: NICHD Neonatal Research Network
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• McNamara PJ, Chock VY, Rahde-Bischoff A, Gabrio J, Johnson KJ, Harmon HM, Montoya-Williams D, Colaizy TT, Katheria AC, Ines F, Sorrells K, Battersby C, Levy PT, Rysavy MA, Bhombal S, Laughon MM, Carper B, Hintz SR, Das A, Bell EF. Evaluating the efficacy and safety of milrinone for prevention of post-patent ductus arteriosus closure syndrome (the MIDAS trial) in extremely preterm infants: a multicentre, double-masked, randomised, placebo-controlled trial. BMJ Open. 2025 Aug 26;15(8):e105018. doi: 10.1136/bmjopen-2025-105018.

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: October 31, 2024
• First Submitted That Met QC Criteria: November 5, 2024
• First Posted (Actual): November 8, 2024

Study Record Updates

• Last Update Posted (Actual): April 20, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Cardiotonic Agents; Vasodilator Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Milrinone
• Other Study ID Numbers: NICHD-NRN-0066

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No