Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus

Study Overview
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Brief Summary
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Multicentric, double-blind clinical trial, which will evaluate the efficacy of iv paracetamol versus standard treatment with ibuprofen in the closure of patent ductus arteriosus in the preterm newborn. Secondarily, we intend to compare the safety of both treatments, increase our knowledge about the pharmacokinetics, pharmacodynamics and pharmacogenetics of paracetamol and ibuprofen in the neonatal period and make a pharmacoeconomic assessment of the use of both drugs.

Detailed Description
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Those newborns ≤ 30 weeks of gestational age who are diagnosed in the first 2 weeks of hemodynamically significant ductus arteriosus and who do not meet any exclusion criteria will be eligible to participate in the study. The PARACETAMOL group will receive intravenous doses of 15 mg/kg administered every 6h for 3 days (up to a maximum of 2 courses, i.e. 6 days). The IBUPROFEN group (control group) will receive the usual treatment, this is an initial dose of 10 mg/kg followed by 5 mg/kg intravenously at 24 and 48 hours after the first (all three doses are considered a treatment course), up a maximum of 2 courses). A daily echocardiographic control will be performed to evaluate the closure of the ductus. If the ductus remains open and with significant clinical repercussion after completing a 3-day course of treatment, another batch of 3 doses of the same treatment will be administered. If medical treatment fails after two courses (6 days), the possibility of administering a batch of Ibuprofen at usual doses in both groups with the intention of offering standard treatment to all patients will be considered. Once the medical treatment with both drugs is completed if the ductus remains significant, the surgical closure will be carried out.

Official Title
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Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus: a Randomized Clinical Trial

Conditions
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Patent Ductus Arteriosus After Premature Birth

Intervention / Treatment
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* Drug: Paracetamol
* Drug: Ibuprofen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written Informed consent of parents/guardians Gestacional Age ≤30 weeks Postnatal age ≤ 2 weeks Need for ventilatory support Born in participating hospital/arrival to them within the period of application of the treatment 1 st episode of hemodynamically significant Patent Ductus Arteriosus Exclusion Criteria: Major congenital malformations or chromosomopathies Refusal to participate and / or sign the informed consent. Impossibility or erroneous randomization Participation in another clinical trial with drugs Diuresis less than 1 ml / kg / h for 8 h prior to treatment Greater than 1.8 mg / dl Creatinine Platelets below 50,000 / uL Active bleeding (tracheal, gastrointestinal and renal) Intraventricular hemorrhage recently (48h) (grades 3-4) Severe hyperbilirubinemia Liver failure or severe coagulopathy Active necrotizing enterocolitis or intestinal perforation Septic shock Imminent death

Ages Eligible for Study
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Maximum Age: 14 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paracetamol<br>Intravenous paracetamol 15 mg/kg/6h for 3 or 6 days | Drug: Paracetamol<br>* Intravenous paracetamol 15 mg/kg/6h<br>|
| Active Comparator: Ibuprofen<br>Intravenous ibuprofen 10 mg/kg/24 h (day 1) and 5 mg/kg/24h (day 2 and 3) for 3 or 6 days | Drug: Ibuprofen<br>* Intravenous ibuprofen 10 mg/kg/24h (day 1) and 5 mg/kg/24h (day 2 and 3)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of closure of the hsPDA after treatment with paracetamol (experimental drug) versus ibuprofen (control drug). | It will include the closure rate after the first course of treatment, considered as ductus diameter &lt; 1 mm monitored by echocardiography performed by a pediatric cardiology specialist. | 24-48 hours after the completion of study intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for a second course of treatment |  | from randomization until discharge, an average of 2 months | 
| Closure rate after two treatment courses |  | from randomization until discharge, an average of 2 months | 
| Need for rescue treatment after two courses of treatment |  | from randomization until discharge, an average of 2 months | 
| Reopening rate after closure |  | from randomization until discharge, an average of 2 months | 
| Closing rate after reopening |  | from randomization until discharge, an average of 2 months | 
| Time required until closing |  | from randomization until discharge, an average of 2 months | 
| Need for surgical ligation |  | from randomization until discharge, an average of 2 months | 
| Incidence of early complications | oliguria, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, hyperbilirubinemia, gastrointestinal bleeding or perforation | from randomization until discharge, an average of 2 months | 
| Incidence of late complications | bronchopulmonary dysplasia, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of the newborn, neurodevelopmental assessment, sepsis, death | from randomization until 2 years | 
| Pharmacodynamics model of paracetamol in the context of hsPDA: Maximum Plasma Concentration [Cmax] | Relation of effectiveness/adverse reactions to serum levels | 24-48 hours after the completion of study intervention | 
| Pharmacodynamics model of paracetamol in the context of hsPDA: Minimum Plasma Concentration [Cmin] | Relation of effectiveness/adverse reactions to serum levels | 24-48 hours after the completion of study intervention | 
| Pharmacodynamics model of paracetamol in the context of hsPDA: Area Under the Curve [AUC]) | Relation of effectiveness/adverse reactions to serum levels | 24-48 hours after the completion of study intervention | 
| Pharmacodynamics model of paracetamol in the context of hsPDA: urine metabolites | Quantification of metabolites in urine and its relationship with drug elimination/metabolism | 24-48 hours after the completion of study intervention | 
| Pharmacogenetics of paracetamol | Genetic polymorphisms in TFAP2B, TGFBR2, EPAS1, MD-2 and GM2A genes related to efficacy/occurrence of adverse reactions | 24-48 hours after the completion of study intervention | 
| Price-effectiveness ratio. Cost-effectiveness analysis depending on the efficiency obtained in the treatment. |  | from randomization until discharge, an average of 2 months | 
| Genotoxicity mesured by %DNA damage |  | from randomization until discharge, an average of 2 months |