Early Treatment Versus Expectant Management of PDA in Preterm Infants

Study Overview
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Brief Summary
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Patent ductus arteriosus (PDA) in very preterm newborns is associated with severe neonatal mor-bidity: intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), necrotizing en-terocolitis (NEC), retinopathy of prematurity (ROP). Existing methods of management PDA do not reduce the incidence of these diseases. The efficacy of cyclooxygenase inhibitors (COX) which are currently the standard of treatment in extreme preterm infants is about 70-80%. COX inhibitors have significant side effects. On the other hand, surgical ligation of the ductus arteriosus is associated with deterioration due to cardio-pulmonary problems and long-term complications. Paracetamol has been proposed for treatment of hemodynamically significant PDA because it has a different mecha-nism of action compared with COX inhibitors and a better safety profile. Recently, expectant approach has becoming more popular, although there is not enough evidence to support it. The objective of this study is to investigate whether in preterm infants, born at a GA less than 32 weeks, with a PDA (diameter > 1.5 mm) at a postnatal age of < 72 h, an expectant management is non-inferior to early treatment with regard to the composite of mortality and/or severe morbidity.

Official Title
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Randomized Non-inferiority Trial of Early Treatment Versus Expectant Management of Patent Ductus Arteriosus in Preterm Infants

Conditions
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Patent Ductus Arteriosus

Intervention / Treatment
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* Drug: Ibuprofen
* Drug: Paracetamol
* Other: Expectant Management


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age < 32 weeks Birthweight <1500 g Age less than 72 hours PDA diameter > 1.5 mm Signed informed consent obtained from both parents Exclusion Criteria: Birthweight ≥ 1500 g and/or gestation age ≥ 32 weeks Lack of informed consent of the parents Congenital heart defect, other than PDA and/or patent foramen ovale (PFO) The presence of a clinically apparent hemorrhagic syndrome Any intraventricular hemorrhage (IVH) in the first 48 hours or IVH grade 3-4 A platelet count of < 50,000/mm3 A serum creatinine concentration of > 110 μmol/L Oliguria <1 ml/kg/h Suspected/apparent NEC Suspected/apparent lung hypoplasia

Ages Eligible for Study
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Maximum Age: 3 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rectal ibuprofen<br>Early treatment of PDA that starts within the first 3 days of life using rectal ibuprofen q24h for 3 days, dosages: 20 mg/kg + 10 mg/kg + 10 mg/kg | Drug: Ibuprofen<br>* In the medical treatment arm the in-tention is to close the ductus arteriosus.<br>* Other names: Cyclooxygenase Inhibitor;|
| Active Comparator: Intravenous paracetamol<br>Early treatment of PDA that starts within the first 3 days of life using intravenous paraceta-mol 15 mg/kg q6h for 3 days | Drug: Paracetamol<br>* In the medical treatment arm the in-tention is to close the ductus arteriosus.<br>* Other names: Infulgan, Acetaminophen;|
| Sham Comparator: Expectant Treatment<br>Expectant PDA management is characterized as 'watchful waiting'. No intervention is initiated with the intention to close a PDA unless defi-nitely needed based of the predefined infant's condition. | Other: Expectant Management<br>* Expectative PDA management is character-ized as 'watchful waiting'. No intervention is initiated with the intention to close a PDA.<br>* Other names: Conservative management;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of bronchopulmonary dysplasia (BPD) or mortality at 36 weeks postmenstrual age (PMA) |  | 36 weeks PMA | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PDA re-opening rate | PDA re-opening after echocardiographically documented closure | Day 1 up to 3 month | 
| Closure rate of PDA within a week after the first and second course of pharmacological treatment |  | Participants will be evaluated at the end of first and second course, at an expected avarage of 10 days of life | 
| The need for surgical ductus closure |  | Day 1 up to 3 month | 
| Duration of any ventilation assist | The ventilation assist time period | Day 1 up to 3 month | 
| Duration of oxygen supplementation | Days on supplement oxygen | Day 1 up to 3 month | 
| Age of administration of full volume of enteral nutrition |  | Day 1 up to 3 month | 
| Incidence of oliguria |  | In the first 14 days of life | 
| Incidence of hypotension |  | Day 1 up to 3 month | 
| Incidence of BPD |  | 36 weeks PMA | 
| Mortality rate |  | 36 weeks PMA | 
| Incidence of severe intraventricular hemorrhage |  | 28-days since birth | 
| Incidence of necrotizing enterocolitis (Bell stage ≥ IIa) |  | 36 weeks PMA | 
| Incidence of periventricular leukomalacia |  | 36 weeks PMA | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ibuprofen, Paracetamol, Expectant management, PDA