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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
Last Update Posted : May 4, 2018
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

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 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 Type : Interventional  (Clinical Trial)
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 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 : December 2013
Actual Primary Completion Date : June 2017
Actual Study Completion Date : June 2017

Resource links provided by the National Library of Medicine

U.S. FDA Resources

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.
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).



Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. duration of different types of respiratory support (ventilation, CPAP, cannula) [ Time Frame: up to 20 weeks of age ]
  2. duration of gavage feeding assistance [ Time Frame: up to 20 weeks of age ]
  3. incidence of necrotizing enterocolitis or spontaneous perforation [ Time Frame: up to 20 weeks of age ]


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Ages Eligible for Study:   up to 14 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

  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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01958320


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

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01958320     History of Changes
Other Study ID Numbers: RC4
First Posted: October 9, 2013    Key Record Dates
Last Update Posted: May 4, 2018
Last Verified: May 2018

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:
Ductus Arteriosus, Patent
Enterocolitis
Enterocolitis, Necrotizing
Intestinal Perforation
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities