PDA:TOLERATE: Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT01958320
• Collaborator: (none)
• Enrollment: 202
• Locations: 18
• Arms: 2
• Duration (Months): 42
• Patients Per Site: 11.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The primary goal of the trial is to compare two different Patent Ductus Arteriosus (PDA) treatment approaches: 1) an "early treatment" approach or 2) a "conservative" approach. For the purposes of the study infants will be enrolled if they are delivered before 28 weeks gestation and have a moderate/large PDA present at 5-7 days after birth.

The hypothesis is: treatment of a moderate size patent ductus arteriosus (PDA) will decrease the time needed for assisted respiratory support, diuretic therapy, and gavage feeding assistance, in addition to decreasing the incidence of ductus ligations or need for future outpatient cardiology follow-up appointments. The investigators hypothesize that one or more of these benefits will occur without an increase in the time taken to achieve full enteral feedings or in the incidence of necrotizing enterocolitis (NEC) or spontaneous intestinal perforations (SIP).The investigators will be comparing the effectiveness of early pharmacologic treatment with a control group of conservatively managed infants who will only receive treatment if they meet specific criteria for "rescue treatment".

Condition or Disease	Intervention/Treatment	Phase
Patent Ductus Arteriosus; Surgery; Necrotizing Enterocolitis; Intestinal Perforation	Other: pharmacologic treatment of the PDA; Other: no pharmacologic treatment of the PDA; Drug: NSAID	Phase 2

Detailed Description

Prior studies showed that, if a moderate/large Patent Ductus Arteriosus (PDA) is still present at 5 days after birth (among infants delivered at 23 and 0/7 to 25 and 6/7 weeks gestation) or at 7 days after birth (among infants delivered at 26 and 0/7 to 27 and 6/7 weeks gestation), it will persist for at least another 4-12 weeks if it is left untreated.

Study Design

• Study Type: Interventional
• Actual Enrollment: 202 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Early routine, mandated PDA treatment versus Conservative treatment only if Rescue criteria are metEarly routine, mandated PDA treatment versus Conservative treatment only if Rescue criteria are met
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus in Preterm infants-a Multicenter Trial
• Study Start Date: Dec 1, 2013
• Actual Primary Completion Date: Jun 1, 2017
• Actual Study Completion Date: Jun 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Early treatment Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up.	Other: pharmacologic treatment of the PDA; Following randomization, infants will be treated with medications used to produce PDA closure.; Drug: NSAID; Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment
Active Comparator: Conservative Treatment Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up.	Other: no pharmacologic treatment of the PDA; Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).; Drug: NSAID; Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment

Outcome Measures

Primary Outcome Measures

1. Number of Infants Who Undergo in Hospital PDA Ligations or Who Have an Open Ductus at the Time of Discharge (That Need Future Outpatient Cardiology Follow-up Visits) [through hospital discharge (approximately 6 months unless death occurs first)]

   Number of infants who undergo in hospital PDA ligations or who have an open ductus at the time of discharge (that need future outpatient cardiology follow-up visits)

Secondary Outcome Measures

1. Duration of Gavage Feeding Assistance [up to 20 weeks of age]

   duration of gavage feeding assistance

2. Incidence of Necrotizing Enterocolitis or Spontaneous Perforation [through hospital discharge (approximately 6 months unless death occurs first)]

   incidence of necrotizing enterocolitis or spontaneous perforation

3. the Average Daily Weight Gain [up to 20 weeks of age]

   the average daily weight gain

4. Incidence of Bronchopulmonary Dysplasia or Death [determined between 36-37 weeks corrected age]

   incidence of bronchopulmonary dysplasia or death

5. Incidence of Death [through hospital discharge (approximately 6 months unless death occurs first)]

   incidence of death

6. the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment [10 days after enrollment]

   the incidence of persistent moderate-to-large PDA shunt 10 days after enrollment The echocardiographic studies included two dimensional imaging, M-mode, color flow mapping and Doppler interrogation as previously described. A moderate-to-large PDA was defined by a ductus internal diameter ≥ 1.5mm (or PDA:left pulmonary artery diameter ratio ≥0.5) and one or more of the following echocardiographic criteria: a) left atrium-to-aortic root (LA/Ao) ratio ≥1.6, b) ductus flow velocity ≤2.5m/sec or mean pressure gradient across the ductus ≤8mm, c) left pulmonary artery diastolic flow velocity > 0.2 m/sec, and/or d) reversed diastolic flow in the descending aorta. Ductus that failed to meet these criteria were considered to be "constricted" (small or closed) and not eligible for enrollment or treatment.

7. the Incidence of Rescue Treatment Eligibility Criteria Met [through hospital discharge (approximately 6 months unless death occurs first)]

   Infants were eligible for rescue PDA drug treatment if they met one or more of the following prespecified "Rescue" criteria: 1) Inotrope-dependent hypotension for at least 3 days. 2) Oliguria that persisted for at least 2 days with no obvious cause, other than the moderate PDA, to explain the condition. 3) Requirement for gavage feedings beyond 35 weeks corrected age due to increased work of breathing. 4) Respiratory support needed after the following postnatal ages that surpassed specific minimal ventilation and FiO2 requirements: >15 days (if still required intubation and FiO2 >0.30), >20 days (if still required intubation and FiO2 ≤0.30; or still required Nasal CPAP or Nasal ventilation and FiO2 >0.30), >30 days (if still required Nasal CPAP or Nasal ventilation and FiO2 0.25-0.30), and >45 days (if still required Nasal CPAP or Nasal ventilation and FiO2 <0.25).

8. Number of Infants Receiving ≥ 14 Days of Diuretic Treatment [through hospital discharge (approximately 6 months unless death occurs first)]

   number of infants receiving ≥ 14 days of diuretic treatment

Other Outcome Measures

1. Number of Infants Who Received Dopamine for ≥3 Days [through hospital discharge (approximately 6 months unless death occurs first)]

   number of infants who received dopamine for ≥3 days

2. Incidence of Bacteremia [through hospital discharge (approximately 6 months unless death occurs first)]

   incidence of bacteremia

3. Incidence of Pulmonary Hemorrhage [through hospital discharge (approximately 6 months unless death occurs first)]

   incidence of pulmonary hemorrhage

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Days to 14 Days
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

This will be a prospective randomized, multi-center, controlled trial that will enroll infants delivered between 23 & 0/7 - 27 & 6/7 weeks gestation:

1. infants must be between 5-14 days old (if delivered between 23 and 0/7 - 25 and 6/7 weeks) or 7-14 days old (if delivered between 26 & 0/7 - 27 & 6/7 weeks) and

2. have a "moderate size PDA" (defined as a PDA on echocardiogram that has at least one of the following criteria: internal ductus diameter ≥1.5 mm/kg (or PDA:LPA ratio ≥0.5), ductus flow velocity ≤2.5 m/s or mean pressure gradient across the ductus <8 mm, LA/Ao ratio ≥1.5, left pulmonary artery diastolic (or mean) flow velocity >0.2 (or

0.42) m/sec, respectively, and/or reversed diastolic flow in the descending aorta)(13, 68, 69) and

1. are receiving respiratory support consisting of either mechanical ventilation, nasal CPAP, SiPAP, or nasal cannula flow ≥2 L/min.

Exclusion Criteria:

prior treatment with indomethacin, ibuprofen, or acetaminophen, contraindications for the use of indomethacin, ibuprofen, or acetaminophen (these include: hydrocortisone administration within 24 hrs, urine output < 1 ml/kg/h during the preceding 8 h, serum creatinine level >1.6 mg/dl, platelet count <50, 000/mm3, abnormal coagulation studies, or total bilirubin concentration (in mg/dL) > 8 x weight (in kg)), chromosomal anomalies, congenital or acquired gastrointestinal anomalies, prior episode of necrotizing enterocolitis or intestinal perforation.

-

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego	San Diego	California	United States	92093-0934
2	Sharp Mary Birch Hospital for Women and Newborns	San Diego	California	United States	92123
3	University of California San Francisco	San Francisco	California	United States	94143
4	Mednax Neonatology of San Jose/Pediatrix Medical Group	San Jose	California	United States	92868
5	Kaiser Permanente Santa Clara	Santa Clara	California	United States	95051
6	South Miami Hospital	Miami	Florida	United States	33143
7	University of Chicago Medicine	Chicago	Illinois	United States	60637
8	Northshore University Health System	Evanston	Illinois	United States	60201
9	Johns Hopkins University	Baltimore	Maryland	United States	21218
10	Mayo Clinic	Rochester	Minnesota	United States	55902
11	Morristown Medical Center	Morristown	New Jersey	United States	07960
12	Columbia University	New York	New York	United States	10032
13	Providence St Vincent Medical Center	Portland	Oregon	United States	97225
14	University Hospital, Umea, Sweden	Umea		Sweden
15	Ankara University School of Medicine Children's Hospital	Ankara		Turkey
16	Sisli Hamidiye Etfal Training and Research Hospital	Istanbul		Turkey
17	Inonu University School of Medicine Turgut Ozal Medical Center	Malatya		Turkey
18	University of Glasgow, Royal Hospital for Sick Children	Glasgow	Scotland	United Kingdom	G38SJ

Sponsors and Collaborators

• University of California, San Francisco

Investigators

• Principal Investigator: Ronald Clyman, MD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 19, 2013

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01958320
• Other Study ID Numbers: RC4
• First Posted: Oct 9, 2013
• Last Update Posted: Nov 30, 2018
• Last Verified: Nov 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of California, San Francisco: patent ductus arteriosus; patent ductus arteriosus ligation; necrotizing enterocolitis; spontaneous intestinal perforation
• Additional relevant MeSH terms: Enterocolitis; Enterocolitis, Necrotizing; Intestinal Perforation; Ductus Arteriosus, Patent

Study Results

Participant Flow

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Period Title: Overall Study
STARTED	104	98
COMPLETED	104	98
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Early Treatment	Conservative Treatment	Total
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).	Total of all reporting groups
Overall Participants	104	98	202
Age (Count of Participants)
<=18 years	104 100%	98 100%	202 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (days after birth) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days after birth]	8.1 (2.1)	8.3 (2.3)	8.2 (2.2)
Sex: Female, Male (Count of Participants)
Female	56 53.8%	55 56.1%	111 55%
Male	48 46.2%	43 43.9%	91 45%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	25 24%	19 19.4%	44 21.8%
Not Hispanic or Latino	79 76%	79 80.6%	158 78.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 1.9%	0 0%	2 1%
Asian	12 11.5%	14 14.3%	26 12.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	14 13.5%	11 11.2%	25 12.4%
White	76 73.1%	73 74.5%	149 73.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Sweden	7 6.7%	7 7.1%	14 6.9%
Turkey	14 13.5%	15 15.3%	29 14.4%
United States	80 76.9%	72 73.5%	152 75.2%
United Kingdom	3 2.9%	4 4.1%	7 3.5%
Gestation (weeks of gestation) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [weeks of gestation]	25.7 (1.2)	25.9 (1.1)	25.8 (1.2)

Outcome Measures

1. Primary Outcome

Title	Number of Infants Who Undergo in Hospital PDA Ligations or Who Have an Open Ductus at the Time of Discharge (That Need Future Outpatient Cardiology Follow-up Visits)
Description	Number of infants who undergo in hospital PDA ligations or who have an open ductus at the time of discharge (that need future outpatient cardiology follow-up visits)
Time Frame	through hospital discharge (approximately 6 months unless death occurs first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Count of Participants [Participants]	33 31.7%	38 38.8%

2. Secondary Outcome

Title	Duration of Gavage Feeding Assistance
Description	duration of gavage feeding assistance
Time Frame	up to 20 weeks of age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Median (Inter-Quartile Range) [days]	76	80

3. Secondary Outcome

Title	Incidence of Necrotizing Enterocolitis or Spontaneous Perforation
Description	incidence of necrotizing enterocolitis or spontaneous perforation
Time Frame	through hospital discharge (approximately 6 months unless death occurs first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Count of Participants [Participants]	17 16.3%	19 19.4%

4. Secondary Outcome

Title	the Average Daily Weight Gain
Description	the average daily weight gain
Time Frame	up to 20 weeks of age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Mean (Standard Deviation) [gm/kg/day]	22.5 (4.8)	22.8 (4.6)

5. Secondary Outcome

Title	Incidence of Bronchopulmonary Dysplasia or Death
Description	incidence of bronchopulmonary dysplasia or death
Time Frame	determined between 36-37 weeks corrected age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Count of Participants [Participants]	60 57.7%	56 57.1%

6. Secondary Outcome

Title	Incidence of Death
Description	incidence of death
Time Frame	through hospital discharge (approximately 6 months unless death occurs first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Count of Participants [Participants]	20 19.2%	10 10.2%

7. Secondary Outcome

Title	the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment
Description	the incidence of persistent moderate-to-large PDA shunt 10 days after enrollment The echocardiographic studies included two dimensional imaging, M-mode, color flow mapping and Doppler interrogation as previously described. A moderate-to-large PDA was defined by a ductus internal diameter ≥ 1.5mm (or PDA:left pulmonary artery diameter ratio ≥0.5) and one or more of the following echocardiographic criteria: a) left atrium-to-aortic root (LA/Ao) ratio ≥1.6, b) ductus flow velocity ≤2.5m/sec or mean pressure gradient across the ductus ≤8mm, c) left pulmonary artery diastolic flow velocity > 0.2 m/sec, and/or d) reversed diastolic flow in the descending aorta. Ductus that failed to meet these criteria were considered to be "constricted" (small or closed) and not eligible for enrollment or treatment.
Time Frame	10 days after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Count of Participants [Participants]	43 41.3%	78 79.6%

8. Secondary Outcome

Title	the Incidence of Rescue Treatment Eligibility Criteria Met
Description	Infants were eligible for rescue PDA drug treatment if they met one or more of the following prespecified "Rescue" criteria: 1) Inotrope-dependent hypotension for at least 3 days. 2) Oliguria that persisted for at least 2 days with no obvious cause, other than the moderate PDA, to explain the condition. 3) Requirement for gavage feedings beyond 35 weeks corrected age due to increased work of breathing. 4) Respiratory support needed after the following postnatal ages that surpassed specific minimal ventilation and FiO2 requirements: >15 days (if still required intubation and FiO2 >0.30), >20 days (if still required intubation and FiO2 ≤0.30; or still required Nasal CPAP or Nasal ventilation and FiO2 >0.30), >30 days (if still required Nasal CPAP or Nasal ventilation and FiO2 0.25-0.30), and >45 days (if still required Nasal CPAP or Nasal ventilation and FiO2 <0.25).
Time Frame	through hospital discharge (approximately 6 months unless death occurs first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Count of Participants [Participants]	32 30.8%	61 62.2%

9. Secondary Outcome

Title	Number of Infants Receiving ≥ 14 Days of Diuretic Treatment
Description	number of infants receiving ≥ 14 days of diuretic treatment
Time Frame	through hospital discharge (approximately 6 months unless death occurs first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Count of Participants [Participants]	36 34.6%	45 45.9%

10. Other Pre-specified Outcome

Title	Number of Infants Who Received Dopamine for ≥3 Days
Description	number of infants who received dopamine for ≥3 days
Time Frame	through hospital discharge (approximately 6 months unless death occurs first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Count of Participants [Participants]	14 13.5%	25 25.5%

11. Other Pre-specified Outcome

Title	Incidence of Bacteremia
Description	incidence of bacteremia
Time Frame	through hospital discharge (approximately 6 months unless death occurs first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Count of Participants [Participants]	31 29.8%	21 21.4%

12. Other Pre-specified Outcome

Title	Incidence of Pulmonary Hemorrhage
Description	incidence of pulmonary hemorrhage
Time Frame	through hospital discharge (approximately 6 months unless death occurs first)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Treatment	Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.	Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
Measure Participants	104	98
Count of Participants [Participants]	2 1.9%	2 2%

Adverse Events

Time Frame	until hospital discharge (approximately 6 months unless death occurs first)
Adverse Event Reporting Description	The definition of serious adverse event in this trial only included the following: Necrotizing enterocolitis and death.
Arm/Group Title	Early Treatment		Conservative Treatment
Arm/Group Description	Infants randomized to the early treatment group will receive "pharmacologic treatment of the PDA" to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. pharmacologic treatment of the PDA: Following randomization, infants will be treated with medications used to produce PDA closure.		Infants randomized to the Conservative Treatment approach will receive "no pharmacologic treatment of the PDA" but will be followed to determine if they meet criteria for later PDA "rescue treatment" (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. no pharmacologic treatment of the PDA: Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).
All Cause Mortality
	Early Treatment		Conservative Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/104 (19.2%)		10/98 (10.2%)
Serious Adverse Events
	Early Treatment		Conservative Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/104 (16.3%)		19/98 (19.4%)
Gastrointestinal disorders
necrotizing enterocolitis	17/104 (16.3%)		19/98 (19.4%)
Other (Not Including Serious) Adverse Events
	Early Treatment		Conservative Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

See detailed limitations in published manuscript

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.