Clinical Trial to Evaluate Two Guidelines for the Administration of Ibuprofen in the Treatment of Persistent Ductus Arteriosus Eco-guided: Impact in the Intestinal Prognosis

Study Overview
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Brief Summary
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Persistent ductus arteriosus (DA) is a common entity in the premature newborn and is associated with high morbidity and mortality. There is still controversy about which is the best treatment for its closure. Children with AD who receive pharmacological treatment present more frequently than other premature children, necrotizing enterocolitis or isolated intestinal perforation. At the present time, the conventional treatment of DA consists in the administration of intravenous ibuprofen, slow bolus in 3 daily doses 10-5-5 mg / kg / day. Recently, it has been observed that treatment with ibuprofen in continuous iv infusion for 3 days seems to be more effective in closing DA than conventional treatment for 3 days with the same dose but in slow iv bolus. This experimental treatment reduced the incidence of associated necrotizing enterocolitis. Our group demonstrated in a previous pilot trial that the guided treatment with echocardiography (EchoG) of DA with ibuprofen compared with conventional treatment, allows to reduce the number of doses to the patient. The EchoG treatment thus presents a potential reduction of side effects associated with medication, this resulted in a tendency to have a lower incidence of necrotising enterocolitis in the experimental group. This multicenter clinical trial aims to test the hypothesis that the combination of 2 experimental treatments, the use of ibuprofen in continuous perfusion and EchoG, reduces the incidence of digestive side effects (necrotising enterocolitis or isolated intestinal perforation) compared to the treatment also guided by echocardiography but slow bolus iv.

Official Title
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Phase III Clinical Trial, Randomized, Multicentre, Double Blind to Evaluate Two Guidelines for the Administration of Ibuprofen in the Treatment of Persistent Ductus Arteriosus Eco-guided: Impact in the Intestinal Prognosis

Conditions
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Persistent Ductus Arteriosus

Intervention / Treatment
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* Drug: Ibuprofen in continuous (24 hours) iv infusion and EchoG
* Drug: IV bolus Ibuprofen slow (15 minutes) and EchoG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infants with less 33 weeks of gestational age DA ≥ 1.5 mm with decision to start pharmacological treatment Informed consent signed by the legal representative Exclusion Criteria: Consent denied Presence of serious congenital alterations Congenital heart disease Contraindication for the administration of IB: oligoanuria (diuresis <1cc / kg / h), bleeding severe recent intraventricular (HIV grade III or extensive periventricular hemorrhagic infarction), serum creatinine> 1.5 mg / dl or clinical suspicion of intestinal ischemia.

Ages Eligible for Study
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Minimum Age: 0 Minutes
Maximum Age: 33 Weeks

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
Interventional Model Description: Administration schedule A: Ibuprofen in continuous iv infusion and EchoG. Each cycle will be 3 doses. Administration schedule B: slow iv bolus Ibuprofen and EchoG. Each cycle will be 3 doses.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibuprofen in continuous (24 hours) iv infusion and EchoG<br>The first dose of ibuprofen will be 10 mg / kg to be administered as a continuous infusion for 24 hours. An echocardiogram will be performed before each of the following 2 doses of 5 mg / Kg and will only be administered if it meets echocardiographic criteria that indicate open DA (observation of ductus permeability with color Doppler regardless of its size). Each dose will be administered as a 24-hour continuous infusion. | Drug: Ibuprofen in continuous (24 hours) iv infusion and EchoG<br>* The first dose of ibuprofen will be 10 mg / kg to be administered as a continuous infusion for 24 hours. An echocardiogram will be performed before each of the following 2 doses of 5 mg / Kg and will only be administered if it meets echocardiographic criteria that indicate open DA (observation of ductus permeability with color Doppler regardless of its size). Each dose will be administered as a 24-hour continuous infusion.<br>|
| Experimental: IV bolus Ibuprofen slow (15 minutes) and EchoG<br>The first dose of ibuprofen of 10 mg / Kg to be administered in slow iv bolus (15 minutes). Before each of the following 2 doses of 5 mg / Kg, echocardiography will be performed and will only be administered if it meets the echocardiographic criteria indicated by open DA (observation of ductus permeability in color Doppler regardless of its size). Each dose will be administered in iv boluses in 15 minutes | Drug: IV bolus Ibuprofen slow (15 minutes) and EchoG<br>* The first dose of ibuprofen of 10 mg / Kg to be administered in slow iv bolus (15 minutes). Before each of the following 2 doses of 5 mg / Kg, echocardiography will be performed and will only be administered if it meets the echocardiographic criteria indicated by open DA (observation of ductus permeability in color Doppler regardless of its size). Each dose will be administered in iv boluses in 15 minutes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change the incidence of necrotizing enterocolitis or isolated intestinal perforation in preterm infants receiving treatment for closure of AD with ibuprofen in continuous IV perfusion and EchoG vs iv and EchoG boluses | Change the incidence of necrotizing enterocolitis or isolated intestinal perforation in preterm infants receiving treatment for closure of AD with ibuprofen in continuous IV perfusion and EchoG vs iv and EchoG boluses | 40 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Identify genetic polymorphisms asociated to refractory medical treatment of AD and in those most vulnerable to presenting necrotizing enterocolitis or isolated intestinal perforation. | Identify genetic polymorphisms in patients refractory to medical treatment of AD and in those most vulnerable to presenting necrotizing enterocolitis or isolated intestinal perforation. | Day 0(Visit 1) |