Clinical trial NCT01958320: Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus
Official title: Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus in Preterm infants-a Multicenter Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Patent Ductus Arteriosus
Surgery
Necrotizing Enterocolitis
Intestinal Perforation
Keywords: patent ductus arteriosus
patent ductus arteriosus ligation
necrotizing enterocolitis
spontaneous intestinal perforation
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2013-10-09
Enrollment: 202
Sex: ALL
Minimum age (years): 5
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Early routine, mandated PDA treatment versus Conservative treatment only if Rescue criteria are met
Primary purpose: TREATMENT

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.

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:

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.

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   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.

   -

Primary outcomes:
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)
timeFrame: through hospital discharge (approximately 6 months unless death occurs first)
Secondary outcomes:
measure: Duration of Gavage Feeding Assistance
timeFrame: up to 20 weeks of age
measure: Incidence of Necrotizing Enterocolitis or Spontaneous Perforation
timeFrame: through hospital discharge (approximately 6 months unless death occurs first)
measure: the Average Daily Weight Gain
timeFrame: up to 20 weeks of age
measure: Incidence of Bronchopulmonary Dysplasia or Death
timeFrame: determined between 36-37 weeks corrected age
measure: Incidence of Death
timeFrame: through hospital discharge (approximately 6 months unless death occurs first)
measure: the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment
timeFrame: 10 days after enrollment
measure: the Incidence of Rescue Treatment Eligibility Criteria Met
timeFrame: through hospital discharge (approximately 6 months unless death occurs first)
measure: Number of Infants Receiving ≥ 14 Days of Diuretic Treatment
timeFrame: through hospital discharge (approximately 6 months unless death occurs first)
Other outcomes:
measure: Number of Infants Who Received Dopamine for ≥3 Days
timeFrame: through hospital discharge (approximately 6 months unless death occurs first)
measure: Incidence of Bacteremia
timeFrame: through hospital discharge (approximately 6 months unless death occurs first)
measure: Incidence of Pulmonary Hemorrhage
timeFrame: through hospital discharge (approximately 6 months unless death occurs first)
Locations:
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: San Diego
country: United States
facility: Sharp Mary Birch Hospital for Women and Newborns
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: San Jose
country: United States
facility: Mednax Neonatology of San Jose/Pediatrix Medical Group
state: California
city: Santa Clara
country: United States
facility: Kaiser Permanente Santa Clara
state: California
city: Miami
country: United States
facility: South Miami Hospital
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Evanston
country: United States
facility: Northshore University Health System
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: New York
country: United States
facility: Columbia University
state: New York
city: Portland
country: United States
facility: Providence St Vincent Medical Center
state: Oregon
city: Umea
country: Sweden
facility: University Hospital, Umea, Sweden
city: Ankara
country: Turkey
facility: Ankara University School of Medicine Children's Hospital
city: Istanbul
country: Turkey
facility: Sisli Hamidiye Etfal Training and Research Hospital
city: Malatya
country: Turkey
facility: Inonu University School of Medicine Turgut Ozal Medical Center
city: Glasgow
country: United Kingdom
facility: University of Glasgow, Royal Hospital for Sick Children
state: Scotland
Study officials:
affiliation: University of California, San Francisco
name: Ronald Clyman, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.