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

Primary Purpose

Patent Ductus Arteriosus, Surgery, Necrotizing Enterocolitis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
pharmacologic treatment of the PDA
no pharmacologic treatment of the PDA
NSAID
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Patent Ductus Arteriosus focused on measuring patent ductus arteriosus, patent ductus arteriosus ligation, necrotizing enterocolitis, spontaneous intestinal perforation

Eligibility Criteria

5 Days - 14 Days (Child)All SexesDoes not accept healthy volunteers

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.

    -

Sites / Locations

  • University of California San Diego
  • Sharp Mary Birch Hospital for Women and Newborns
  • University of California San Francisco
  • Mednax Neonatology of San Jose/Pediatrix Medical Group
  • Kaiser Permanente Santa Clara
  • South Miami Hospital
  • University of Chicago Medicine
  • Northshore University Health System
  • Johns Hopkins University
  • Mayo Clinic
  • Morristown Medical Center
  • Columbia University
  • Providence St Vincent Medical Center
  • University Hospital, Umea, Sweden
  • Ankara University School of Medicine Children's Hospital
  • Sisli Hamidiye Etfal Training and Research Hospital
  • Inonu University School of Medicine Turgut Ozal Medical Center
  • University of Glasgow, Royal Hospital for Sick Children

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Early treatment

Conservative Treatment

Arm 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.

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.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Duration of Gavage Feeding Assistance
duration of gavage feeding assistance
Incidence of Necrotizing Enterocolitis or Spontaneous Perforation
incidence of necrotizing enterocolitis or spontaneous perforation
the Average Daily Weight Gain
the average daily weight gain
Incidence of Bronchopulmonary Dysplasia or Death
incidence of bronchopulmonary dysplasia or death
Incidence of Death
incidence of death
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.
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).
Number of Infants Receiving ≥ 14 Days of Diuretic Treatment
number of infants receiving ≥ 14 days of diuretic treatment

Full Information

First Posted
October 4, 2013
Last Updated
November 28, 2018
Sponsor
University of California, San Francisco
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1. Study Identification

Unique Protocol Identification Number
NCT01958320
Brief Title
Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus
Acronym
PDA:TOLERATE
Official Title
Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus in Preterm infants-a Multicenter Trial
Study Type
Interventional

2. Study Status

Record Verification Date
November 2018
Overall Recruitment Status
Completed
Study Start Date
December 2013 (undefined)
Primary Completion Date
June 2017 (Actual)
Study Completion Date
June 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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".
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Patent Ductus Arteriosus, Surgery, Necrotizing Enterocolitis, Intestinal Perforation
Keywords
patent ductus arteriosus, patent ductus arteriosus ligation, necrotizing enterocolitis, spontaneous intestinal perforation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Early routine, mandated PDA treatment versus Conservative treatment only if Rescue criteria are met
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
202 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Early treatment
Arm Type
Experimental
Arm 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.
Arm Title
Conservative Treatment
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
pharmacologic treatment of the PDA
Intervention Description
Following randomization, infants will be treated with medications used to produce PDA closure.
Intervention Type
Other
Intervention Name(s)
no pharmacologic treatment of the PDA
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
NSAID
Intervention Description
Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment
Primary Outcome Measure Information:
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)
Secondary Outcome Measure Information:
Title
Duration of Gavage Feeding Assistance
Description
duration of gavage feeding assistance
Time Frame
up to 20 weeks of age
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)
Title
the Average Daily Weight Gain
Description
the average daily weight gain
Time Frame
up to 20 weeks of age
Title
Incidence of Bronchopulmonary Dysplasia or Death
Description
incidence of bronchopulmonary dysplasia or death
Time Frame
determined between 36-37 weeks corrected age
Title
Incidence of Death
Description
incidence of death
Time Frame
through hospital discharge (approximately 6 months unless death occurs first)
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
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)
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)
Other Pre-specified Outcome Measures:
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)
Title
Incidence of Bacteremia
Description
incidence of bacteremia
Time Frame
through hospital discharge (approximately 6 months unless death occurs first)
Title
Incidence of Pulmonary Hemorrhage
Description
incidence of pulmonary hemorrhage
Time Frame
through hospital discharge (approximately 6 months unless death occurs first)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Days
Maximum Age & Unit of Time
14 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
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: 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 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 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. -
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ronald Clyman, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92093-0934
Country
United States
Facility Name
Sharp Mary Birch Hospital for Women and Newborns
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Mednax Neonatology of San Jose/Pediatrix Medical Group
City
San Jose
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Kaiser Permanente Santa Clara
City
Santa Clara
State/Province
California
ZIP/Postal Code
95051
Country
United States
Facility Name
South Miami Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33143
Country
United States
Facility Name
University of Chicago Medicine
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Northshore University Health System
City
Evanston
State/Province
Illinois
ZIP/Postal Code
60201
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21218
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55902
Country
United States
Facility Name
Morristown Medical Center
City
Morristown
State/Province
New Jersey
ZIP/Postal Code
07960
Country
United States
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Providence St Vincent Medical Center
City
Portland
State/Province
Oregon
ZIP/Postal Code
97225
Country
United States
Facility Name
University Hospital, Umea, Sweden
City
Umea
Country
Sweden
Facility Name
Ankara University School of Medicine Children's Hospital
City
Ankara
Country
Turkey
Facility Name
Sisli Hamidiye Etfal Training and Research Hospital
City
Istanbul
Country
Turkey
Facility Name
Inonu University School of Medicine Turgut Ozal Medical Center
City
Malatya
Country
Turkey
Facility Name
University of Glasgow, Royal Hospital for Sick Children
City
Glasgow
State/Province
Scotland
ZIP/Postal Code
G38SJ
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
30340932
Citation
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.
Results Reference
result
PubMed Identifier
31255386
Citation
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.
Results Reference
derived
PubMed Identifier
30850756
Citation
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.
Results Reference
derived

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Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus

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