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