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| Name | Class |
|---|---|
| Instituto de Investigacion Sanitaria La Fe | OTHER |
| Spanish Clinical Research Network - SCReN | NETWORK |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Paracetamol | Experimental | Intravenous paracetamol 15 mg/kg/6h for 3 or 6 days |
|
| Ibuprofen | Active Comparator | Intravenous ibuprofen 10 mg/kg/24 h (day 1) and 5 mg/kg/24h (day 2 and 3) for 3 or 6 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Paracetamol | Drug | Intravenous paracetamol 15 mg/kg/6h |
| |
| Ibuprofen |
| 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 < 1 mm monitored by echocardiography performed by a pediatric cardiology specialist. | 24-48 hours after the completion of study intervention |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Maximo Vento Torres, PhD, MD | Hospital Universitario La Fe | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Reina Sofía | Córdoba | Cordoba | Spain | |||
| Hospital Universitario de Cabueñes |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24223740 | Background | Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLoS One. 2013 Nov 4;8(11):e77888. doi: 10.1371/journal.pone.0077888. eCollection 2013. | |
| 22065264 | Background | Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics. 2011 Dec;128(6):e1618-21. doi: 10.1542/peds.2011-0359. Epub 2011 Nov 7. |
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| ID | Term |
|---|---|
| D000082 | Acetaminophen |
| D007052 | Ibuprofen |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 |
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| Drug |
Intravenous ibuprofen 10 mg/kg/24h (day 1) and 5 mg/kg/24h (day 2 and 3) |
|
| 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 |
| Gijón |
| Gijón |
| Spain |
| Hospital Materno-Infantil (Hospital Regional Carlos Haya) Málaga: | Málaga | Málaga | Spain |
| Hospital Universitari i Politècnic La Fe | Valencia | Valencia | 46026 | Spain |
| 24359938 | Background | Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, Canpolat FE, Dilmen U. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr. 2014 Mar;164(3):510-4.e1. doi: 10.1016/j.jpeds.2013.11.008. Epub 2013 Dec 18. |
| 27698754 | Background | Yang B, Gao X, Ren Y, Wang Y, Zhang Q. Oral paracetamol vs. oral ibuprofen in the treatment of symptomatic patent ductus arteriosus in premature infants: A randomized controlled trial. Exp Ther Med. 2016 Oct;12(4):2531-2536. doi: 10.3892/etm.2016.3676. Epub 2016 Sep 6. |
| 26244949 | Background | Dash SK, Kabra NS, Avasthi BS, Sharma SR, Padhi P, Ahmed J. Enteral paracetamol or Intravenous Indomethacin for Closure of Patent Ductus Arteriosus in Preterm Neonates: A Randomized Controlled Trial. Indian Pediatr. 2015 Jul;52(7):573-8. doi: 10.1007/s13312-015-0677-z. |
| 25471090 | Background | Sancak S, Gokmen Yildirim T, Topcuoglu S, Yavuz T, Karatekin G, Ovali F. Oral versus intravenous paracetamol: which is better in closure of patent ductus arteriosus in very low birth weight infants? J Matern Fetal Neonatal Med. 2016;29(1):135-9. doi: 10.3109/14767058.2014.989829. Epub 2014 Dec 23. |
| 24941212 | Background | El-Khuffash A, Jain A, Corcoran D, Shah PS, Hooper CW, Brown N, Poole SD, Shelton EL, Milne GL, Reese J, McNamara PJ. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr Res. 2014 Sep;76(3):238-44. doi: 10.1038/pr.2014.82. Epub 2014 Jun 18. |
| 32766181 | Derived | Garcia-Robles A, Gimeno Navarro A, Serrano Martin MDM, Parraga Quiles MJ, Parra Llorca A, Poveda-Andres JL, Vento Torres M, Aguar Carrascosa M. Paracetamol vs. Ibuprofen in Preterm Infants With Hemodynamically Significant Patent Ductus Arteriosus: A Non-inferiority Randomized Clinical Trial Protocol. Front Pediatr. 2020 Jul 17;8:372. doi: 10.3389/fped.2020.00372. eCollection 2020. |
| Aniline Compounds |
| D000588 | Amines |
| D010666 | Phenylpropionates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |