Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus

Surgery Clinical Trial

— PDA:TOLERATE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01958320
• Other study ID #: RC4
• Status: Completed
• Phase: Phase 2
• Start date: December 2013
• Est. completion date: June 2017

Study information

• Verified date: November 2018
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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".

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 202
• Est. completion date: June 2017
• Est. primary completion date: June 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 14 Days

Eligibility

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.

Related Conditions & MeSH terms

• Ductus Arteriosus, Patent
• Enterocolitis
• Enterocolitis, Necrotizing
• Intestinal Perforation
• Necrotizing Enterocolitis
• Patent Ductus Arteriosus
• Surgery

Intervention

Other:
• pharmacologic treatment of the PDA
Following randomization, infants will be treated with medications used to produce PDA closure.
• 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

Locations

Country	Name	City	State
Sweden	University Hospital, Umea, Sweden	Umea
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
United Kingdom	University of Glasgow, Royal Hospital for Sick Children	Glasgow	Scotland
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Chicago Medicine	Chicago	Illinois
United States	Northshore University Health System	Evanston	Illinois
United States	South Miami Hospital	Miami	Florida
United States	Morristown Medical Center	Morristown	New Jersey
United States	Columbia University	New York	New York
United States	Providence St Vincent Medical Center	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Sharp Mary Birch Hospital for Women and Newborns	San Diego	California
United States	University of California San Diego	San Diego	California
United States	University of California San Francisco	San Francisco	California
United States	Mednax Neonatology of San Jose/Pediatrix Medical Group	San Jose	California
United States	Kaiser Permanente Santa Clara	Santa Clara	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, San Francisco

Countries where clinical trial is conducted

United States,  Sweden,  Turkey,  United Kingdom, 

References & Publications (1)

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, Leo — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)
Other	Incidence of Bacteremia	incidence of bacteremia	through hospital discharge (approximately 6 months unless death occurs first)
Other	Incidence of Pulmonary Hemorrhage	incidence of pulmonary hemorrhage	through hospital discharge (approximately 6 months unless death occurs first)
Primary	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	Duration of Gavage Feeding Assistance	duration of gavage feeding assistance	up to 20 weeks of age
Secondary	Incidence of Necrotizing Enterocolitis or Spontaneous Perforation	incidence of necrotizing enterocolitis or spontaneous perforation	through hospital discharge (approximately 6 months unless death occurs first)
Secondary	the Average Daily Weight Gain	the average daily weight gain	up to 20 weeks of age
Secondary	Incidence of Bronchopulmonary Dysplasia or Death	incidence of bronchopulmonary dysplasia or death	determined between 36-37 weeks corrected age
Secondary	Incidence of Death	incidence of death	through hospital discharge (approximately 6 months unless death occurs first)
Secondary	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
Secondary	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)
Secondary	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)