Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus

NCT01958320 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: RC4
• Study Type: interventional
• Target: 202
• Locations: 4 countries
• Sites: 18

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".

Conditions

Patent Ductus Arteriosus; Surgery; Necrotizing Enterocolitis; Intestinal Perforation

Keywords

patent ductus arteriosus; patent ductus arteriosus ligation; necrotizing enterocolitis; spontaneous intestinal perforation

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Duration of Gavage Feeding Assistance

  up to 20 weeks of age

• Incidence of Necrotizing Enterocolitis or Spontaneous Perforation

  through hospital discharge (approximately 6 months unless death occurs first)

• the Average Daily Weight Gain

  up to 20 weeks of age

• Incidence of Bronchopulmonary Dysplasia or Death

  determined between 36-37 weeks corrected age

• Incidence of Death

  through hospital discharge (approximately 6 months unless death occurs first)

Other Outcomes (3)

• Number of Infants Who Received Dopamine for ≥3 Days

  through hospital discharge (approximately 6 months unless death occurs first)

• Incidence of Bacteremia

  through hospital discharge (approximately 6 months unless death occurs first)

• Incidence of Pulmonary Hemorrhage

  through hospital discharge (approximately 6 months unless death occurs first)

Study Arms (2)

Early treatment

EXPERIMENTAL

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; Drug: NSAID

Conservative Treatment

ACTIVE COMPARATOR

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; Drug: NSAID

Interventions

pharmacologic treatment of the PDA OTHER

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

Early treatment

no pharmacologic treatment of the PDA 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).

Conservative Treatment

NSAID DRUG

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

Conservative Treatment; Early treatment

Eligibility Criteria

• Age: 5 Days - 14 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• This will be a prospective randomized, multi-center, controlled trial that will enroll infants delivered between 23 \& 0/7 - 27 \& 6/7 weeks gestation:
• 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
• 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
• are receiving respiratory support consisting of either mechanical ventilation, nasal CPAP, SiPAP, or nasal cannula flow ≥2 L/min.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (18)

University of California San Diego

San Diego, California, 92093-0934, United States

Location

Sharp Mary Birch Hospital for Women and Newborns

San Diego, California, 92123, United States

Location

University of California San Francisco

San Francisco, California, 94143, United States

Location

Mednax Neonatology of San Jose/Pediatrix Medical Group

San Jose, California, 92868, United States

Location

Kaiser Permanente Santa Clara

Santa Clara, California, 95051, United States

Location

South Miami Hospital

Miami, Florida, 33143, United States

Location

University of Chicago Medicine

Chicago, Illinois, 60637, United States

Location

Northshore University Health System

Evanston, Illinois, 60201, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21218, United States

Location

Mayo Clinic

Rochester, Minnesota, 55902, United States

Location

Morristown Medical Center

Morristown, New Jersey, 07960, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Providence St Vincent Medical Center

Portland, Oregon, 97225, United States

Location

University Hospital, Umea, Sweden

Umeå, Sweden

Location

Ankara University School of Medicine Children's Hospital

Ankara, Turkey (Türkiye)

Location

Sisli Hamidiye Etfal Training and Research Hospital

Istanbul, Turkey (Türkiye)

Location

Inonu University School of Medicine Turgut Ozal Medical Center

Malatya, Turkey (Türkiye)

Location

University of Glasgow, Royal Hospital for Sick Children

Glasgow, Scotland, G38SJ, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 30340932 RESULT

• 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.

  PMID: 31255386 DERIVED

• 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.

  PMID: 30850756 DERIVED

MeSH Terms

Conditions

Ductus Arteriosus, Patent; Enterocolitis, Necrotizing; Intestinal Perforation

Interventions

Anti-Inflammatory Agents, Non-Steroidal

Condition Hierarchy (Ancestors)

Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Enterocolitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Anti-Inflammatory Agents; Therapeutic Uses; Antirheumatic Agents

Limitations and Caveats

See detailed limitations in published manuscript

Results Point of Contact

• Title: Ronald Clyman, MD PI
• Organization: University of California San Francisco

clymanr@peds.ucsf.edu

415-443-9305

Study Officials

• Ronald Clyman, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Early routine, mandated PDA treatment versus Conservative treatment only if Rescue criteria are met

Study Record Dates

• First Submitted: October 4, 2013
• First Posted: October 9, 2013
• Study Start: December 1, 2013
• Primary Completion: June 1, 2017
• Study Completion: June 1, 2017
• Last Updated: November 30, 2018
• Results First Posted: November 30, 2018

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

US (13); TU (3); SE (1); GB (1)