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

Patent Ductus Arteriosus After Premature Birth Clinical Trial

— IBUPAR  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04037514
• Other study ID #: IBUPAR-TRIAL
• Status: Recruiting
• Phase: Phase 3
• Start date: July 7, 2017
• Est. completion date: February 28, 2022

Study information

• Verified date: July 2019
• Source: Instituto de Investigacion Sanitaria La Fe
• Contact: Marta Aguar Carrascosa, PhD, MD
• Phone: 0034 961245686
• Email: maraca[@]alumni.uv.es
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: February 28, 2022
• Est. primary completion date: January 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 14 Days

Eligibility

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

Related Conditions & MeSH terms

• Ductus Arteriosus, Patent
• Patent Ductus Arteriosus After Premature Birth
• Premature Birth

Intervention

Drug:
• Paracetamol
Intravenous paracetamol 15 mg/kg/6h
• Ibuprofen
Intravenous ibuprofen 10 mg/kg/24h (day 1) and 5 mg/kg/24h (day 2 and 3)

Locations

Country	Name	City	State
Spain	Hospital Reina Sofía	Córdoba	Cordoba
Spain	Hospital Universitario de Cabueñes	Gijón
Spain	Hospital Materno-Infantil (Hospital Regional Carlos Haya) Málaga:	Málaga
Spain	Hospital Universitari i Politècnic La Fe	Valencia

Sponsors (3)

Lead Sponsor	Collaborator
Máximo Vento Torres	Instituto de Investigacion Sanitaria La Fe, Spanish Clinical Research Network - CAIBER

Country where clinical trial is conducted

Spain, 

References & Publications (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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2016 Sep 6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Need for a second course of treatment		from randomization until discharge, an average of 2 months
Secondary	Closure rate after two treatment courses		from randomization until discharge, an average of 2 months
Secondary	Need for rescue treatment after two courses of treatment		from randomization until discharge, an average of 2 months
Secondary	Reopening rate after closure		from randomization until discharge, an average of 2 months
Secondary	Closing rate after reopening		from randomization until discharge, an average of 2 months
Secondary	Time required until closing		from randomization until discharge, an average of 2 months
Secondary	Need for surgical ligation		from randomization until discharge, an average of 2 months
Secondary	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
Secondary	Incidence of late complications	bronchopulmonary dysplasia, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of the newborn, neurodevelopmental assessment, sepsis, death	from randomization until 2 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Price-effectiveness ratio. Cost-effectiveness analysis depending on the efficiency obtained in the treatment.		from randomization until discharge, an average of 2 months
Secondary	Genotoxicity mesured by %DNA damage		from randomization until discharge, an average of 2 months