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

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

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.

Study Overview

• Status: Completed
• Conditions: Patent Ductus Arteriosus After Premature Birth
• Intervention / Treatment: Drug: Paracetamol; Drug: Ibuprofen

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.

• Study Type: Interventional
• Enrollment (Actual): 133
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Cordoba
    • Córdoba, Cordoba, Spain
      • Hospital Reina Sofia
  • Gijón
    • Gijón, Gijón, Spain
      • Hospital Universitario de Cabueñes
  • Málaga
    • Málaga, Málaga, Spain
      • Hospital Materno-Infantil (Hospital Regional Carlos Haya) Málaga:
  • Valencia
    • Valencia, Valencia, Spain, 46026
      • Hospital Universitari i Politecnic La Fe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 weeks (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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 < 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

Collaborators and Investigators

• Sponsor: Máximo Vento Torres
• Collaborators: Instituto de Investigacion Sanitaria La Fe; Spanish Clinical Research Network - SCReN
• Investigators: Study Chair: Maximo Vento Torres, PhD, MD, Hospital Universitario La Fe

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2017
• Primary Completion (Actual): December 18, 2024
• Study Completion (Actual): December 18, 2024

Study Registration Dates

• First Submitted: July 23, 2019
• First Submitted That Met QC Criteria: July 26, 2019
• First Posted (Actual): July 30, 2019

Study Record Updates

• Last Update Posted (Estimated): December 18, 2025
• Last Update Submitted That Met QC Criteria: December 10, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Heart Defects, Congenital; Cardiovascular Abnormalities; Premature Birth; Ductus Arteriosus, Patent; Organic Chemicals; Carboxylic Acids; Anilides; Amides; Aniline Compounds; Amines; Acetanilides; Acids, Carbocyclic; Phenylpropionates; Acetaminophen; Ibuprofen
• Other Study ID Numbers: IBUPAR-TRIAL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No