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

Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus in Preterm infants-a Multicenter Trial

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".

Study Overview

• Status: Completed
• Conditions: Necrotizing Enterocolitis; Surgery; Patent Ductus Arteriosus; Intestinal Perforation
• Intervention / Treatment: Other: pharmacologic treatment of the PDA; Drug: NSAID; Other: no pharmacologic treatment of the PDA

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 Type: Interventional
• Enrollment (Actual): 202
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Umea, Sweden
    • University Hospital, Umea, Sweden
• Turkey
  • Ankara, Turkey
    • Ankara University School of Medicine Children's Hospital
  • Istanbul, Turkey
    • Sisli Hamidiye Etfal Training and Research Hospital
  • Malatya, Turkey
    • Inonu University School of Medicine Turgut Ozal Medical Center
• United Kingdom
  • Scotland
    • Glasgow, Scotland, United Kingdom, G38SJ
      • University of Glasgow, Royal Hospital for Sick Children
• United States
  • California
    • San Diego, California, United States, 92123
      • Sharp Mary Birch Hospital for Women and Newborns
    • San Diego, California, United States, 92093-0934
      • University of California San Diego
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • San Jose, California, United States, 92868
      • Mednax Neonatology of San Jose/Pediatrix Medical Group
    • Santa Clara, California, United States, 95051
      • Kaiser Permanente Santa Clara
  • Florida
    • Miami, Florida, United States, 33143
      • South Miami Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medicine
    • Evanston, Illinois, United States, 60201
      • Northshore University Health System
  • Maryland
    • Baltimore, Maryland, United States, 21218
      • Johns Hopkins University
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Mayo Clinic
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Oregon
    • Portland, Oregon, United States, 97225
      • Providence St Vincent Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 days to 2 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

3. 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.

   -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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.	Drug: NSAID; Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Gavage Feeding Assistance	duration of gavage feeding assistance	up to 20 weeks of age
Incidence of Necrotizing Enterocolitis or Spontaneous Perforation	incidence of necrotizing enterocolitis or spontaneous perforation	through hospital discharge (approximately 6 months unless death occurs first)
the Average Daily Weight Gain	the average daily weight gain	up to 20 weeks of age
Incidence of Bronchopulmonary Dysplasia or Death	incidence of bronchopulmonary dysplasia or death	determined between 36-37 weeks corrected age
Incidence of Death	incidence of death	through hospital discharge (approximately 6 months unless death occurs first)
the Incidence of Persistent Moderate-to-large PDA Shunt 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.	10 days after enrollment
the Incidence of Rescue Treatment Eligibility Criteria Met	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).	through hospital discharge (approximately 6 months unless death occurs first)
Number of Infants Receiving ≥ 14 Days of Diuretic Treatment	number of infants receiving ≥ 14 days of diuretic treatment	through hospital discharge (approximately 6 months unless death occurs first)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Infants Who Received Dopamine for ≥3 Days	number of infants who received dopamine for ≥3 days	through hospital discharge (approximately 6 months unless death occurs first)
Incidence of Bacteremia	incidence of bacteremia	through hospital discharge (approximately 6 months unless death occurs first)
Incidence of Pulmonary Hemorrhage	incidence of pulmonary hemorrhage	through hospital discharge (approximately 6 months unless death occurs first)

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Hakansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J, Nelson K, Wickremasinghe A, Dong L, Hassinger DC, Aucott SW, Hayashi M, Heuchan AM, Carey WA, Derrick M, Fernandez E, Sankar M, Leone T, Perez J, Serize A; PDA-TOLERATE (PDA: TO LEave it alone or Respond And Treat Early) Trial Investigators. PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age. J Pediatr. 2019 Feb;205:41-48.e6. doi: 10.1016/j.jpeds.2018.09.012. Epub 2018 Oct 16.
• Liebowitz M, Katheria A, Sauberan J, Singh J, Nelson K, Hassinger DC, Aucott SW, Kaempf J, Kimball A, Fernandez E, Carey WA, Perez J, Serize A, Wickremasinghe A, Dong L, Derrick M, Wolf IS, Heuchan AM, Sankar M, Bulbul A, Clyman RI; PDA-TOLERATE (PDA: TOLEave it alone or Respond And Treat Early) Trial Investigators. Lack of Equipoise in the PDA-TOLERATE Trial: A Comparison of Eligible Infants Enrolled in the Trial and Those Treated Outside the Trial. J Pediatr. 2019 Oct;213:222-226.e2. doi: 10.1016/j.jpeds.2019.05.049. Epub 2019 Jun 27.
• Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Hakansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J, Nelson K, Wickremasinghe A, Dong L, Hassinger DC, Aucott SW, Hayashi M, Heuchan AM, Carey WA, Derrick M, Wolf IS, Kimball A, Sankar M, Leone T, Perez J, Serize A, Clyman RI. Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial (NCT01958320). J Perinatol. 2019 May;39(5):599-607. doi: 10.1038/s41372-019-0347-4. Epub 2019 Mar 8.

Study record dates

Study Major Dates

• Study Start: December 1, 2013
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: October 4, 2013
• First Submitted That Met QC Criteria: October 8, 2013
• First Posted (Estimate): October 9, 2013

Study Record Updates

• Last Update Posted (Actual): November 30, 2018
• Last Update Submitted That Met QC Criteria: November 28, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: necrotizing enterocolitis; patent ductus arteriosus; patent ductus arteriosus ligation; spontaneous intestinal perforation
• Additional Relevant MeSH Terms: Digestive System Diseases; Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Enterocolitis; Enterocolitis, Necrotizing; Ductus Arteriosus, Patent; Intestinal Perforation
• Other Study ID Numbers: RC4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

What data in particular will be shared? Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

What other documents will be available? Study Protocol

When will data be available (start and end dates)? Beginning 9 months and ending 36 months following article publication.

With whom? Researchers who provide a methodologically sound proposal.

For what types of analyses? To achieve aims in the approved proposal.

Proposals should be directed to clymanr@ucsf.edu. To gain access, data requestors will need to sign a data access agreement.

• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal. o achieve aims in the approved proposal. Proposals should be directed to clymanr@ucsf.edu. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No