Early Treatment Versus Expectative Management of PDA in Preterm Infants

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Brief Title

Early Treatment Versus Expectative Management of PDA in Preterm Infants

Official Title

Multi-center, Randomized Non-inferiority Trial of Early Treatment Versus Expectative Management of Patent Ductus Arteriosus in Preterm Infants (BeNeDuctus Trial - Belgium Netherlands Ductus Trial)

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.
    

Detailed Description

      After obtainment of informed consent the first echocardiographic evaluation is performed at a
      postnatal age of 24-72 hours. In absence of exclusion criteria patients will only be
      randomized when a PDA is present, the transductal diameter measures >1.5 mm and a blood flow
      pattern with a predominantly left-to-right shunt is observed. Randomization will assign the
      neonate to either the medical treatment (COXi) arm or the expectative PDA management arm.

      It is essential that neonatal management is similar in both arms with the exception of the
      prescription of COX-inhibition and routine echocardiographic examination after a course of
      COXi in the medical treatment arm.

      Medical treatment arm When the patient is allocated to the medical treatment arm
      COX-inhibition is prescribed and started as soon as possible, but no later than 3 hours after
      the echocardiogram.

      The investigators prefer to use Ibuprofen (IBU) for COX-inhibition in this study. Aside from
      the above mentioned reasons the investigators are confronted with an actual lack of
      availability of indomethacin in most centers in the Netherlands and Belgium. However,
      Indomethacin (INDO) can be prescribed for medical ductal closure if this is preferred by a
      participating center.

      The dosing schemes for IBU and INDO are according the local guidelines. For the first week of
      life the birth weight is used for calculation of the COXi dosage. After a postnatal age of 7
      days the actual weight is used for dose calculation, except when the actual weight is still
      less than the birthweight.

      The treatment described above is considered standard of care in many NICU's worldwide. It
      should be noted that there is no modification of the commonly advised usage of IBU in this
      study. There are reports that suggest that an high dose of IBU might be more effective in
      ductal closure in preterm infants, especially in those less than 27 weeks' gestation.
      However, in a systematic review one refrained from recommendations regarding high dose IBU
      because of the limited number of patients enrolled in studies.

      The preferred route of administration of IBU is intravenously. However, this is at the
      disposal of the attending physician, since enteral administration appears at least as
      effective.

      Echocardiographic reevaluation is performed at least 12 hours after the last (3rd) dose of
      the first COXi course. If the ductus arteriosus is found to be closed, no further analysis or
      treatment is needed regarding the ductus arteriosus. A ductus arteriosus is considered to be
      closed when it can't be visualized using color Doppler imaging or when the transductal
      diameter measures less than 0.5 mm.

      When the ductus arteriosus hasn't closed, a second course of COX-inhibition is started at
      least 24 hours after the third dose of the first course. COXi dosages are similar to the
      first course.

      Twelve to 24 hours after the last dose of the second course (6th gift) echocardiography is
      performed. If the ductus arteriosus is found to be closed, no further analysis or treatment
      is needed regarding the ductus arteriosus.

      When the duct failed to close after two courses of COXi (6 doses in total) and the PDA is
      judged to be still hemodynamically significant, ductal ligation can be considered, only when
      the so-called 'ligation criteria' are met.

      Expectative PDA management arm Patients randomized to the expectative management arm will not
      receive any COXi and PDA management in this group can be characterized as "watchful waiting".
      This is not a unique approach, since a restrictive approach towards a PDA is increasingly
      used in many centers worldwide without the observation of an increased risk of neonatal
      mortality and morbidity, such as severe chronic lung disease (CLD), intraventricular
      hemorrhage (IVH), NEC and retinopathy of prematurity (ROP).

      It is essential that neonatal management is similar in both study arms with the exception of
      the prescription of COXi and echocardiography at the end of the drug course in the medical
      treatment arm. It is of the upmost importance that NO extra interventions are to be
      undertaken with the intention to conservatively prevent or treat a (suspected) PDA in the
      expectative arm, such as fluid restriction and diuretics for that reason. Moreover, it should
      be noted that there is insufficient evidence that fluid restriction and/or diuretics are of
      any benefit in patients with a (suspected) PDA.

      When during the first week the attending physician is of the opinion that the patient is in
      danger, when it's deprived from treatment with COXi, open label treatment can only be
      considered when the 'open label criteria' are met.
    


Study Type

Interventional


Primary Outcome

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

Secondary Outcome

 Short term sequelae of cardiovascular failure

Condition

Patent Ductus Arteriosus

Intervention

Ibuprofen

Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

564

Start Date

December 23, 2016

Completion Date

June 2021

Primary Completion Date

December 2020

Eligibility Criteria

        Inclusion Criteria:

          -  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

        Exclusion Criteria:

          -  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
      

Gender

All

Ages

N/A - 3 Days

Accepts Healthy Volunteers

No

Contacts

Willem P de Boode, MD PhD, +31 24 361 44 30, [email protected]

Location Countries

Belgium

Location Countries

Belgium

Administrative Informations


NCT ID

NCT02884219

Organization ID

843002622


Responsible Party

Sponsor

Study Sponsor

Radboud University

Collaborators

 ZonMw: The Netherlands Organisation for Health Research and Development

Study Sponsor

Willem P de Boode, MD PhD, Principal Investigator, Radboud University


Verification Date

April 2020