A Phase 3 interventional study of Active Treatment and Expectant Management in Infant, Premature, Patent Ductus Arteriosus and Infant, Newborn, Diseases, sponsored by NICHD Neonatal Research Network. Active, not recruiting at 19 sites in United States. Open to participants aged 48 Hours to 21 Days. Per ClinicalTrials.gov, last updated 2026-05-12.
Sponsored by NICHD Neonatal Research Network · Phase 3, Interventional, and Treatment
Estimate the risks and benefits of active treatment versus expectant management of a symptomatic patent ductus arteriosus (sPDA) in premature infants.
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).
sPDA, as defined as:
Exclusion Criteria:
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.
Other: Active Treatment
Infants assigned to the expectant management group will receive indomethacin or ibuprofen if cardiopulmonary compromise occurs.
Other: Expectant Management
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.
Infants assigned to the expectant management group will receive indomethacin or ibuprofen if cardiopulmonary compromise occurs.
Death or Bronchopulmonary Dysplasia (BPD) at 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.
Time frame: Randomization to 36 weeks PMA
Mortality at 36 Weeks PMA
mortality assessed at 36 week postmenstrual age
Time frame: birth to 36 week postmenstrual age
Mortality Before Discharge
mortality assessed prior to hospital discharge
Time frame: birth to 120 days of life
Bronchopulmonary Dysplasia - Physiological Test
BPD defined by the physiologic test of oxygen therapy
Time frame: birth to 36 week postmenstrual age
Bronchopulmonary Dysplasia - NIH Consensus Definition
BPD defined by the NIH consensus definition of moderate or severe
Time frame: birth to 36 week postmenstrual age
Necrotizing Enterocolitis (NEC) at 36 Weeks PMA
Proven NEC, no surgery, Stages IIA, IIB, or IIIA AND proven, surgery, Stage IIIB
Time frame: birth to 36 weeks post menstrual age
Retinopathy of Prematurity at 36 Weeks PMA
Stage 3 or worse in either eye AND as any intervention therapy-retinal ablation, scleral buckle/vitrectomy, avastin or other anti-VEGF drug
Time frame: birth to 36 weeks post menstrual age
Receipt of Therapies Designed to Close the PDA
Defined as ligation or cardiac catheterization
Time frame: birth to 120 days
Weight at 36 Weeks PMA
Weight assessed at 36 weeks post menstrual age
Time frame: birth to 36 weeks post menstrual age
Height at 36 Weeks PMA
Height assessed at 36 weeks post menstrual age
Time frame: birth to 36 weeks post menstrual age
Head Circumference at 36 Weeks PMA
Head Circumference assessed at 36 weeks post menstrual age
Time frame: birth to 36 weeks post menstrual age
Necrotizing Enterocolitis (NEC) at Status (2 Years)
Proven NEC, no surgery, Stages IIA, IIB, or IIIA AND proven, surgery, Stage IIIB
Time frame: 26 months corrected age
Retinopathy of Prematurity at Status (2 Years)
Stage 3 or worse in either eye AND as any intervention therapy-retinal ablation, scleral buckle/vitrectomy, avastin or other anti-VEGF drug
Time frame: 26 months corrected age
Weight at Status (2 Years)
Weight assessed at status (2 years)
Time frame: 26 months corrected age
Height at Status (2 Years)
Height assessed at status (2 years)
Time frame: 26 months corrected age
Head Circumference at Status (2 Years)
Head Circumference assessed at status (2 years)
Time frame: 26 months corrected age
Neurodevelopmental Impairment (NDI) at Status (2 Years)
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.
Time frame: 26 months corrected age
| Milestone | Active Treatment Group | Expectant Management Group |
|---|---|---|
| Started | 240 | 242 |
| Completed | 213 | 223 |
| Not completed | 27 | 19 |
| Withdrew: Death | 23 | 10 |
| Withdrew: Withdrawal by subject | 4 | 8 |
| Withdrew: Withdrew consent for any use of data | 0 | 1 |
mortality assessed at 36 week postmenstrual age
Results for this outcome have not been posted.
mortality assessed prior to hospital discharge
Results for this outcome have not been posted.
BPD defined by the physiologic test of oxygen therapy
Results for this outcome have not been posted.
BPD defined by the NIH consensus definition of moderate or severe
Results for this outcome have not been posted.
Proven NEC, no surgery, Stages IIA, IIB, or IIIA AND proven, surgery, Stage IIIB
Results for this outcome have not been posted.
Stage 3 or worse in either eye AND as any intervention therapy-retinal ablation, scleral buckle/vitrectomy, avastin or other anti-VEGF drug
Results for this outcome have not been posted.
Defined as ligation or cardiac catheterization
Results for this outcome have not been posted.
Weight assessed at 36 weeks post menstrual age
Results for this outcome have not been posted.
Proven NEC, no surgery, Stages IIA, IIB, or IIIA AND proven, surgery, Stage IIIB
Results for this outcome have not been posted.
Stage 3 or worse in either eye AND as any intervention therapy-retinal ablation, scleral buckle/vitrectomy, avastin or other anti-VEGF drug
Results for this outcome have not been posted.
Weight assessed at status (2 years)
Results for this outcome have not been posted.
Height assessed at status (2 years)
Results for this outcome have not been posted.
Head Circumference assessed at status (2 years)
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
| Participants | Active Treatment Group | Expectant Management Group |
|---|---|---|
| Yes | 191 | 195 |
| No | 49 | 46 |
Height assessed at 36 weeks post menstrual age
Results for this outcome have not been posted.
Head Circumference assessed at 36 weeks post menstrual age
Results for this outcome have not been posted.
Collected over Adverse events are reported from time of randomization to 36 completed weeks PMA.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Active Treatment Group | 23/240 (9.6%) | 43/240 (17.9%) | 3/240 (1.3%) |
| Expectant Management Group | 10/241 (4.1%) | 32/241 (13.3%) | 9/241 (3.7%) |
| Event | Active Treatment Group | Expectant Management Group |
|---|---|---|
| Necrotising enterocolitis neonatalGastrointestinal disorders | 19/240 | 17/241 |
| Sepsis neonatalInfections and infestations | 6/240 | 4/241 |
| Septic shockInfections and infestations | 3/240 | 0/241 |
| Renal failureRenal and urinary disorders | 3/240 | 0/241 |
| Neonatal respiratory failureRespiratory, thoracic and mediastinal disorders | 0/240 | 3/241 |
| Neonatal intestinal perforationGastrointestinal disorders | 2/240 | 1/241 |
| Neonatal respiratory distress syndromeRespiratory, thoracic and mediastinal disorders | 1/240 | 2/241 |
| Pneumonia escherichiaInfections and infestations | 1/240 | 0/241 |
| Enterobacter pneumoniaInfections and infestations | 1/240 | 0/241 |
| Staphylococcal sepsisInfections and infestations | 1/240 | 0/241 |
| Event | Active Treatment Group | Expectant Management Group |
|---|---|---|
| Necrotising enterocolitis neonatalGastrointestinal disorders | 1/240 | 4/241 |
| Renal failureRenal and urinary disorders | 0/240 | 2/241 |
| Pulmonary haemorrhage neonatalRespiratory, thoracic and mediastinal disorders | 1/240 | 0/241 |
| Splenic infarctionBlood and lymphatic system disorders | 1/240 | 0/241 |
| Neonatal pneumoniaInfections and infestations | 0/240 | 1/241 |
| Neonatal sinus bradycardiaCardiac disorders | 0/240 | 1/241 |
| Neonatal hypotensionVascular disorders | 0/240 | 1/241 |
One infant was randomized but withdrew consent for use of any data. This infant is excluded from all analyses.
| Age, Continuous(Weeks) | Active Treatment Group | Expectant Management Group | Total |
|---|---|---|---|
| Median | 25.6 (24.3 to 27.3) | 25.6 (24.6 to 27.0) | 25.6 (24.4 to 27.1) |
| Sex: Female, Male(Participants) | Active Treatment Group | Expectant Management Group | Total |
|---|---|---|---|
| Female | 117 | 120 | 237 |
| Male | 123 | 121 | 244 |
| Race (NIH/OMB)(Participants) | Active Treatment Group | Expectant Management Group | Total |
|---|---|---|---|
| American Indian or Alaska Native | 1 | 1 | 2 |
| Asian | 7 | 9 | 16 |
| Native Hawaiian or Other Pacific Islander | 1 | 1 | 2 |
| Black or African American | 82 | 93 | 175 |
| White | 120 | 112 | 232 |
| More than one race | 5 | 7 | 12 |
| Unknown or Not Reported | 24 | 18 | 42 |
| Ethnicity (NIH/OMB)(Participants) | Active Treatment Group | Expectant Management Group | Total |
|---|---|---|---|
| Hispanic or Latino | 58 | 55 | 113 |
| Not Hispanic or Latino | 182 | 186 | 368 |
| Unknown or Not Reported | 0 | 0 | 0 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Per NIH Data Sharing Plan
Supporting information: Study protocol, Sap
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