Management of the PDA Trial

This is a pragmatic randomized multicenter, effectiveness study comparing active treatment of a symptomatic patent ductus arteriosus (sPDA) to expectant management. We hypothesize in premature infants with a sPDA, expectant management reduces the incidence proportion of death or BPD by 10% (from 50% to 40%) when compared to active treatment.

Participants with a sPDA allocated to the active treatment arm will receive intravenous administration of indomethacin or ibuprofen (depending on center preference). The decision to ligate will be left to the clinical team. Participants with a sPDA allocated to the expectant management arm will receive supportive care at the clinical team's discretion and will receive indomethacin/ibuprofen or ligation if the infant develops cardiopulmonary compromise. The decision to ligate will be left to the clinical team.

The primary endpoint for the study will be death or BPD (as assessed by the physiologic definition) at 36 weeks postmenstrual age (PMA).

• Active Treatment (Other): Infants assigned to the active treatment group will receive indomethacin or ibuprofen per their local site usual care dosing and schedule if the infant has a sPDA. The choice of indomethacin or ibuprofen will be left to the center, however, infants may only receive one or the other. If the infant receives both, it will be considered a protocol violation.
• Expectant Management (Other): Infants assigned to the expectant management group will receive indomethacin or ibuprofen if cardiopulmonary compromise occurs.

Primary outcomes

• Death or Bronchopulmonary Dysplasia (BPD) at 36 Weeks PMA [Randomization to 36 weeks PMA]: A composite outcome for infants who were diagnosed with physiologic bronchopulmonary dysplasia (BPD) or died by 36 weeks postmenstrual age (PMA). Physiologic BPD is determined using existing Neonatal Research Network Generic Database criteria at 36 weeks PMA. Infants alive an in hospital are classified based on respiratory status at 36 weeks PMA or by a room air weaning challenge performed between 36 and 37 weeks PMA. Infants who are transferred or discharged before 36 weeks are classified based on the support they are receiving at that time. Infants who died before 36 weeks PMA are not assessed for BPD. Deaths include all-cause deaths between randomization and 36 weeks PMA.

Secondary outcomes

• Mortality at 36 Weeks PMA [birth to 36 week postmenstrual age]: mortality assessed at 36 week postmenstrual age
• Mortality Before Discharge [birth to 120 days of life]: mortality assessed prior to hospital discharge
• Bronchopulmonary Dysplasia - Physiological Test [birth to 36 week postmenstrual age]: BPD defined by the physiologic test of oxygen therapy
• Bronchopulmonary Dysplasia - NIH Consensus Definition [birth to 36 week postmenstrual age]: BPD defined by the NIH consensus definition of moderate or severe
• Necrotizing Enterocolitis (NEC) at 36 Weeks PMA [birth to 36 weeks post menstrual age]: Proven NEC, no surgery, Stages IIA, IIB, or IIIA AND proven, surgery, Stage IIIB
• Retinopathy of Prematurity at 36 Weeks PMA [birth to 36 weeks post menstrual age]: Stage 3 or worse in either eye AND as any intervention therapy-retinal ablation, scleral buckle/vitrectomy, avastin or other anti-VEGF drug
• Receipt of Therapies Designed to Close the PDA [birth to 120 days]: Defined as ligation or cardiac catheterization
• Weight at 36 Weeks PMA [birth to 36 weeks post menstrual age]: Weight assessed at 36 weeks post menstrual age
• Height at 36 Weeks PMA [birth to 36 weeks post menstrual age]: Height assessed at 36 weeks post menstrual age
• Head Circumference at 36 Weeks PMA [birth to 36 weeks post menstrual age]: Head Circumference assessed at 36 weeks post menstrual age

Other outcomes

• Necrotizing Enterocolitis (NEC) at Status (2 Years) [26 months corrected age]: Proven NEC, no surgery, Stages IIA, IIB, or IIIA AND proven, surgery, Stage IIIB
• Retinopathy of Prematurity at Status (2 Years) [26 months corrected age]: Stage 3 or worse in either eye AND as any intervention therapy-retinal ablation, scleral buckle/vitrectomy, avastin or other anti-VEGF drug
• Weight at Status (2 Years) [26 months corrected age]: Weight assessed at status (2 years)
• Height at Status (2 Years) [26 months corrected age]: Height assessed at status (2 years)
• Head Circumference at Status (2 Years) [26 months corrected age]: Head Circumference assessed at status (2 years)
• Neurodevelopmental Impairment (NDI) at Status (2 Years) [26 months corrected age]: Severe NDI will be defined by any of the following: a Bayley Scales of Infant and Toddler Development (BSID) III cognitive score < 70, Gross Motor Functional (GMF) Level of 3-5, blindness (<20/200 vision) or profound hearing loss (inability to understand commands despite amplification); moderate NDI will be defined as a BSID III cognitive score 70-84 and either a GMF level of 2 or a hearing deficit requiring amplification to understand commands or unilateral blindness; mild NDI will be defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMF level 1 or hearing loss not requiring amplification. Normal (no NDI) will be defined by a cognitive score ≥ 85 and absence of any neurosensory deficits.

Sex: All, ages: 48 Hours to 21 Days

Inclusion Criteria:

* Postnatal age 48 hours -21 days
* Infant 22 0/7 to 28 6/7 weeks gestation at birth
* sPDA, as defined as:

  1. Mild, Moderate, or Severe Clinical Criteria with Small or Moderate size PDA on echocardiogram
  2. Mild or Moderate Clinical Criteria with Large PDA on echocardiogram

Exclusion Criteria:

* Cardiopulmonary compromise
* Known congenital heart disease (besides atrial septal defect or ventricular septal defect)
* Known pulmonary malformation (e.g. congenital lobar emphysema, congenital pulmonary adenomatous malformation)
* Any condition which, in the opinion of the investigator, would preclude enrollment

Participant flow

Outcome results

• Mortality at 36 Weeks PMA (Secondary)
• Mortality Before Discharge (Secondary)
• Bronchopulmonary Dysplasia - Physiological Test (Secondary)
• Bronchopulmonary Dysplasia - NIH Consensus Definition (Secondary)
• Necrotizing Enterocolitis (NEC) at 36 Weeks PMA (Secondary)
• Retinopathy of Prematurity at 36 Weeks PMA (Secondary)
• Receipt of Therapies Designed to Close the PDA (Secondary)
• Weight at 36 Weeks PMA (Secondary)
• Necrotizing Enterocolitis (NEC) at Status (2 Years) (Other pre specified)
• Retinopathy of Prematurity at Status (2 Years) (Other pre specified)
• Weight at Status (2 Years) (Other pre specified)
• Height at Status (2 Years) (Other pre specified)
• Head Circumference at Status (2 Years) (Other pre specified)
• Neurodevelopmental Impairment (NDI) at Status (2 Years) (Other pre specified)
• Death or Bronchopulmonary Dysplasia (BPD) at 36 Weeks PMA (Primary), Count of participants, Participants: Active Treatment Group 191; Expectant Management Group 195
• Height at 36 Weeks PMA (Secondary)
• Head Circumference at 36 Weeks PMA (Secondary)

Adverse events

Time frame: Adverse events are reported from time of randomization to 36 completed weeks PMA.

Serious adverse events by term

Other adverse events by term

• Results publication: Laughon MM, Thomas SM, Watterberg KL, Kennedy KA, Keszler M, Ambalavanan N, Davis AS, Slaughter JL, Guillet R, Colaizy TT, Cotten CM, Dhawan MA, Bose CL, Talbert J, Smucny S, Benitz WE, Rysavy MA, Ohls RK, Baserga MC, DeMauro SB, Jaleel M, Jackson WM, Carlo WA, Puopolo KM, Hibbs AM, Katheria A, Sanchez PJ, D'Angio CT, Patel RM, Johnson BA, Chock VY, Bhatt AJ, Merhar SL, Moore R, Laptook AR, Ghavam S, Fuller J, Vyas-Read S, Kicklighter SD, Steinbrekera B, Anderson K, Chandrasekharan PK, Wyckoff MH, Montoya C, Das A, Do B, Chang S, Higgins RD, Walsh MC; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Expectant Management vs Medication for Patent Ductus Arteriosus in Preterm Infants: The PDA Randomized Clinical Trial. JAMA. 2026 Feb 17;335(7):588-599. doi: 10.1001/jama.2025.23330. PMID 41364689

• Study Protocol (PDF, 2020-11-19)
• Statistical Analysis Plan (PDF, 2025-05-08)
• Informed Consent Form (PDF, 2022-04-21)

NIH grants: UG1HD112079, UG1HD112097, UG1HD112100