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

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ClinicalTrials.gov Identifier: NCT01958320
Recruitment Status : Completed
First Posted : October 9, 2013
Results First Posted : November 30, 2018
Last Update Posted : November 30, 2018
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

October 4, 2013
October 9, 2013
October 9, 2018
November 30, 2018
November 30, 2018
December 2013
June 2017   (Final data collection date for primary outcome measure)
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) ]
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)
The primary outcome will be the 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: up to 12 months after hospital discharge ]
Complete list of historical versions of study NCT01958320 on ClinicalTrials.gov Archive Site
  • Duration of Gavage Feeding Assistance [ Time Frame: up to 20 weeks of age ]
    duration of gavage feeding assistance
  • Incidence of Necrotizing Enterocolitis or Spontaneous Perforation [ Time Frame: through hospital discharge (approximately 6 months unless death occurs first) ]
    incidence of necrotizing enterocolitis or spontaneous perforation
  • the Average Daily Weight Gain [ Time Frame: up to 20 weeks of age ]
    the average daily weight gain
  • Incidence of Bronchopulmonary Dysplasia or Death [ Time Frame: determined between 36-37 weeks corrected age ]
    incidence of bronchopulmonary dysplasia or death
  • Incidence of Death [ Time Frame: through hospital discharge (approximately 6 months unless death occurs first) ]
    incidence of death
  • the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment [ Time Frame: 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 [ Time Frame: 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).
  • Number of Infants Receiving ≥ 14 Days of Diuretic Treatment [ Time Frame: through hospital discharge (approximately 6 months unless death occurs first) ]
    number of infants receiving ≥ 14 days of diuretic treatment
  • duration of different types of respiratory support (ventilation, CPAP, cannula) [ Time Frame: up to 20 weeks of age ]
  • Duration of Gavage Feeding Assistance [ Time Frame: up to 20 weeks of age ]
  • incidence of necrotizing enterocolitis or spontaneous perforation [ Time Frame: up to 20 weeks of age ]
  • Number of Infants Who Received Dopamine for ≥3 Days [ Time Frame: through hospital discharge (approximately 6 months unless death occurs first) ]
    number of infants who received dopamine for ≥3 days
  • Incidence of Bacteremia [ Time Frame: through hospital discharge (approximately 6 months unless death occurs first) ]
    incidence of bacteremia
  • Incidence of Pulmonary Hemorrhage [ Time Frame: through hospital discharge (approximately 6 months unless death occurs first) ]
    incidence of pulmonary hemorrhage
Not Provided
 
Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus
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".

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.
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Early routine, mandated PDA treatment versus Conservative treatment only if Rescue criteria are met
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
  • Patent Ductus Arteriosus
  • Surgery
  • Necrotizing Enterocolitis
  • Intestinal Perforation
  • Other: pharmacologic treatment of the PDA
    Following randomization, infants will be treated with medications used to produce PDA closure.
  • 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
  • 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.

    Interventions:
    • Other: pharmacologic treatment of the PDA
    • Drug: NSAID
  • 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.

    Interventions:
    • Other: no pharmacologic treatment of the PDA
    • Drug: NSAID
Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson 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. 2018 Oct 16. pii: S0022-3476(18)31283-6. doi: 10.1016/j.jpeds.2018.09.012. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
202
200
June 2017
June 2017   (Final data collection date for primary outcome measure)

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.

Sexes Eligible for Study: All
up to 14 Days   (Child)
No
Contact information is only displayed when the study is recruiting subjects
Sweden,   Turkey,   United Kingdom,   United States
 
 
NCT01958320
RC4
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: Yes
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.

Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Beginning 9 months and ending 36 months following article publication.
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.
University of California, San Francisco
University of California, San Francisco
Not Provided
Principal Investigator: Ronald Clyman, MD University of California, San Francisco
University of California, San Francisco
November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP