Early Treatment Versus Expectative Management of PDA in Preterm Infants

NCT02884219 | Completed DMC

• 1 other identifier: 843002622
• Study Type: interventional
• Target: 273
• Locations: 2 countries
• Sites: 13

Brief Summary

Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age \<28 weeks and/or a birth weight ≦1000 grams due to a lack of evidence for or against different approaches. A PDA has been associated with serious complications. However, a common finding is that medical and/or surgical treatment of a PDA seems not to reduce the risk of mortality or major morbidity. This might be related to the fact that a substantial portion of preterm infants are treated unnecessarily, because the ductus arteriosus (DA) might have closed spontaneously without any specific intervention. An expectative approach is gaining interest, although convincing evidence is still missing. The objective of this study is to investigate whether in preterm infants \<28 weeks' gestation with a PDA an expectative management is not inferior to early treatment with regard to the composite of mortality and/or necrotizing enterocolitis (NEC) and/or bronchopulmonary dysplasia (BPD) at a postmenstrual age of 36 weeks.

Conditions

Patent Ductus Arteriosus

Keywords

Early treatment; Expectative treatment; Patent ductus arteriosus; Preterm

Outcome Measures

Primary Outcomes (1)

• Composite of mortality, and/or NEC, and/or BPD

  The primary outcome is the composite of mortality, and/or NEC (Bell stage ≥ IIa), and/or BPD, defined as the need for supplemental oxygen need, all at a postmenstrual age of 36 completed weeks.

  At a postmenstrual age of 36 completed weeks

Secondary Outcomes (3)

• Short term sequelae of cardiovascular failure

  Day 1 up to 3 months

• Short term sequelae of adverse events

  Day 1 up to 3 months

• Long-term neurodevelopmental consequences assessed with BSID-III-NL.

  Assessed at an corrected age of 2 years

Study Arms (2)

Early Treatment with cyclooxygenase inhibitors

ACTIVE COMPARATOR

Treatment of PDA that starts within the first 3 days of life using cyclooxygenase-inhibitors (Ibuprofen or Indomethacin)

Drug: Ibuprofen; Drug: Indomethacin

Expectative Treatment

SHAM COMPARATOR

Expectative PDA management is characterized as 'watchful waiting'. No intervention is initiated with the intention to close a PDA.

Other: Expectative Management

Interventions

Ibuprofen DRUG

In the medical treatment (COXi) arm the intention is to close the ductus arteriosus.

Also known as: Cyclooxygenase Inhibitor

Early Treatment with cyclooxygenase inhibitors

Expectative Management OTHER

Expectative PDA management is characterized as 'watchful waiting'. No intervention is initiated with the intention to close a PDA.

Also known as: Conservative management

Expectative Treatment

Indomethacin DRUG

In the medical treatment (COXi) arm the intention is to close the ductus arteriosus.

Also known as: Cyclooxygenase Inhibitor

Early Treatment with cyclooxygenase inhibitors

Eligibility Criteria

• Age: 1 Hour - 3 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• PDA diameter \> 1.5 mm and ductal (predominantly) left-to-right shunt
• Signed informed consent obtained from parent(s) or representative(s)
• Gestational age \< 28 completed weeks

You may not qualify if:

• Contraindication for administration of cyclooxygenase-inhibitors (COXi)
• Persistent pulmonary hypertension (ductal right-to-left shunt ≧33% of cardiac cycle)
• Congenital heart defect, other than PDA and/or patent foramen ovale (PFO)
• Life-threatening congenital defects
• Chromosomal abnormalities and/or congenital anomalies associated with abnormal neurodevelopmental outcome
• Use of COXi prior to randomization

Sponsors & Collaborators

• Radboud University Medical Center: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (13)

University Hospital Antwerp

Antwerp, Belgium

Location

Hôpital Erasme - Clinique Universitaires de Bruxelles

Brussels, Belgium

Location

University Hospital Brussels

Brussels, Belgium

Location

Academic Medical Center

Amsterdam, Netherlands

Location

Free University Amsterdam

Amsterdam, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Leiden University Medical Center

Leiden, Netherlands

Location

Maatricht University Medical Center

Maastricht, Netherlands

Location

Radboudumc Amalia Children's Hospital

Nijmegen, Netherlands

Location

Erasmus Medical Center Rotterdam

Rotterdam, Netherlands

Location

Wilhelmina Children's Hospital/UMCU

Utrecht, Netherlands

Location

Maxima Medical Center

Veldhoven, Netherlands

Location

Isala Kliniek Zwolle

Zwolle, Netherlands

Location

Related Publications (3)

• Hundscheid T, Onland W, Kooi EMW, Vijlbrief DC, de Vries WB, Dijkman KP, van Kaam AH, Villamor E, Kroon AA, Visser R, Mulder-de Tollenaer SM, De Bisschop B, Dijk PH, Avino D, Hocq C, Zecic A, Meeus M, de Baat T, Derriks F, Henriksen TB, Kyng KJ, Donders R, Nuytemans DHGM, Van Overmeire B, Mulder AL, de Boode WP; BeNeDuctus Trial Investigators. Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus. N Engl J Med. 2023 Mar 16;388(11):980-990. doi: 10.1056/NEJMoa2207418. Epub 2022 Dec 6.

  PMID: 36477458 RESULT

• Hundscheid T, Donders R, Onland W, Kooi EMW, Vijlbrief DC, de Vries WB, Nuytemans DHGM, van Overmeire B, Mulder AL, de Boode WP; BeNeDuctus trial study group. Multi-centre, randomised non-inferiority trial of early treatment versus expectant management of patent ductus arteriosus in preterm infants (the BeNeDuctus trial): statistical analysis plan. Trials. 2021 Sep 15;22(1):627. doi: 10.1186/s13063-021-05594-x.

  PMID: 34526095 DERIVED

• Hundscheid T, Onland W, van Overmeire B, Dijk P, van Kaam AHLC, Dijkman KP, Kooi EMW, Villamor E, Kroon AA, Visser R, Vijlbrief DC, de Tollenaer SM, Cools F, van Laere D, Johansson AB, Hocq C, Zecic A, Adang E, Donders R, de Vries W, van Heijst AFJ, de Boode WP. Early treatment versus expectative management of patent ductus arteriosus in preterm infants: a multicentre, randomised, non-inferiority trial in Europe (BeNeDuctus trial). BMC Pediatr. 2018 Aug 4;18(1):262. doi: 10.1186/s12887-018-1215-7.

  PMID: 30077184 DERIVED

Related Links

• Website BeNeDuctus Trial

MeSH Terms

Conditions

Ductus Arteriosus, Patent; Premature Birth

Interventions

Ibuprofen; Cyclooxygenase Inhibitors; Conservative Treatment; Indomethacin

Condition Hierarchy (Ancestors)

Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Therapeutic Uses; Antirheumatic Agents; Therapeutics; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Willem P de Boode, MD PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 1, 2016
• First Posted: August 30, 2016
• Study Start: December 23, 2016
• Primary Completion: March 15, 2022
• Study Completion: March 15, 2022
• Last Updated: July 3, 2023

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will share

Locations

NL (10); BE (3)