Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus

NCT ID: NCT01958320

Last Updated: 2018-11-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 202 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2017-06-30

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.

Conditions

Patent Ductus Arteriosus; Surgery; Necrotizing Enterocolitis; Intestinal Perforation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

pharmacologic treatment of the PDA

Intervention Type: OTHER

Following randomization, infants will be treated with medications used to produce PDA closure.

NSAID

Intervention Type: DRUG

Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment

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.

Group Type: ACTIVE_COMPARATOR

no pharmacologic treatment of the PDA

Intervention Type: OTHER

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).

NSAID

Intervention Type: DRUG

Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment

Interventions

pharmacologic treatment of the PDA

Following randomization, infants will be treated with medications used to produce PDA closure.

Intervention Type: 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).

Intervention Type: OTHER

NSAID

Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment

Intervention Type: DRUG

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.

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• Minimum Eligible Age: 5 Days
• Maximum Eligible Age: 14 Days
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ronald Clyman, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

University of California San Diego

San Diego, California, United States

Sharp Mary Birch Hospital for Women and Newborns

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, United States

South Miami Hospital

Miami, Florida, United States

University of Chicago Medicine

Chicago, Illinois, United States

Northshore University Health System

Evanston, Illinois, United States

Johns Hopkins University

Baltimore, Maryland, United States

Mayo Clinic

Rochester, Minnesota, 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

University Hospital, Umea, Sweden

Umeå, , Sweden

Ankara University School of Medicine Children's Hospital

Ankara, , Turkey (Türkiye)

Sisli Hamidiye Etfal Training and Research Hospital

Istanbul, , Turkey (Türkiye)

Inonu University School of Medicine Turgut Ozal Medical Center

Malatya, , Turkey (Türkiye)

University of Glasgow, Royal Hospital for Sick Children

Glasgow, Scotland, United Kingdom

Countries

United States; Sweden; Turkey (Türkiye); United Kingdom

References

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.

Reference Type: RESULT

PMID: 30340932 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31255386 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30850756 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

RC4

Identifier Type: -

Identifier Source: org_study_id