Patent Ductus Arteriosus After Premature Birth
Conditions
Brief summary
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
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.
Interventions
DRUGParacetamol
Intravenous paracetamol 15 mg/kg/6h
DRUGIbuprofen
Intravenous ibuprofen 10 mg/kg/24h (day 1) and 5 mg/kg/24h (day 2 and 3)
Sponsors
Instituto de Investigacion Sanitaria La Fe
Spanish Clinical Research Network - SCReN
Máximo Vento Torres
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 14 Days
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of closure of the hsPDA after treatment with paracetamol (experimental drug) versus ibuprofen (control drug). | 24-48 hours after the completion of study intervention | It will include the closure rate after the first course of treatment, considered as ductus diameter < 1 mm monitored by echocardiography performed by a pediatric cardiology specialist. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | from randomization until discharge, an average of 2 months | oliguria, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, hyperbilirubinemia, gastrointestinal bleeding or perforation |
| Need for a second course of treatment | from randomization until discharge, an average of 2 months | — |
| Pharmacodynamics model of paracetamol in the context of hsPDA: Maximum Plasma Concentration [Cmax] | 24-48 hours after the completion of study intervention | Relation of effectiveness/adverse reactions to serum levels |
| Pharmacodynamics model of paracetamol in the context of hsPDA: Minimum Plasma Concentration [Cmin] | 24-48 hours after the completion of study intervention | Relation of effectiveness/adverse reactions to serum levels |
| Pharmacodynamics model of paracetamol in the context of hsPDA: Area Under the Curve [AUC]) | 24-48 hours after the completion of study intervention | Relation of effectiveness/adverse reactions to serum levels |
| Pharmacodynamics model of paracetamol in the context of hsPDA: urine metabolites | 24-48 hours after the completion of study intervention | Quantification of metabolites in urine and its relationship with drug elimination/metabolism |
| Pharmacogenetics of paracetamol | 24-48 hours after the completion of study intervention | Genetic polymorphisms in TFAP2B, TGFBR2, EPAS1, MD-2 and GM2A genes related to efficacy/occurrence of adverse reactions |
| 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 | — |
| Incidence of late complications | from randomization until 2 years | bronchopulmonary dysplasia, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of the newborn, neurodevelopmental assessment, sepsis, death |
Countries
Spain
Outcome results
None listed