Clinical trial NCT04037514: Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus
Official title: Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus: a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Patent Ductus Arteriosus After Premature Birth
Lead sponsor: Instituto de Investigacion Sanitaria La Fe
Sponsor class: OTHER
Collaborators: name: Instituto de Investigacion Sanitaria La Fe
name: Spanish Clinical Research Network - SCReN
First posted: 2019-07-30
Enrollment: 300
Sex: ALL
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Rate of closure of the hsPDA after treatment with paracetamol (experimental drug) versus ibuprofen (control drug).
timeFrame: 24-48 hours after the completion of study intervention
Secondary outcomes:
measure: Need for a second course of treatment
timeFrame: from randomization until discharge, an average of 2 months
measure: Closure rate after two treatment courses
timeFrame: from randomization until discharge, an average of 2 months
measure: Need for rescue treatment after two courses of treatment
timeFrame: from randomization until discharge, an average of 2 months
measure: Reopening rate after closure
timeFrame: from randomization until discharge, an average of 2 months
measure: Closing rate after reopening
timeFrame: from randomization until discharge, an average of 2 months
measure: Time required until closing
timeFrame: from randomization until discharge, an average of 2 months
measure: Need for surgical ligation
timeFrame: from randomization until discharge, an average of 2 months
measure: Incidence of early complications
timeFrame: from randomization until discharge, an average of 2 months
measure: Incidence of late complications
timeFrame: from randomization until 2 years
measure: Pharmacodynamics model of paracetamol in the context of hsPDA: Maximum Plasma Concentration [Cmax]
timeFrame: 24-48 hours after the completion of study intervention
measure: Pharmacodynamics model of paracetamol in the context of hsPDA: Minimum Plasma Concentration [Cmin]
timeFrame: 24-48 hours after the completion of study intervention
measure: Pharmacodynamics model of paracetamol in the context of hsPDA: Area Under the Curve [AUC])
timeFrame: 24-48 hours after the completion of study intervention
measure: Pharmacodynamics model of paracetamol in the context of hsPDA: urine metabolites
timeFrame: 24-48 hours after the completion of study intervention
measure: Pharmacogenetics of paracetamol
timeFrame: 24-48 hours after the completion of study intervention
measure: Price-effectiveness ratio. Cost-effectiveness analysis depending on the efficiency obtained in the treatment.
timeFrame: from randomization until discharge, an average of 2 months
measure: Genotoxicity mesured by %DNA damage
timeFrame: from randomization until discharge, an average of 2 months
Other outcomes:
Locations:
city: Córdoba
country: Spain
facility: Hospital Reina Sofía
state: Cordoba
city: Gijón
country: Spain
facility: Hospital Universitario de Cabueñes
city: Málaga
country: Spain
facility: Hospital Materno-Infantil (Hospital Regional Carlos Haya) Málaga:
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
Study officials:
affiliation: Hospital Universitario La Fe
name: Maximo Vento Torres, PhD, MD
role: STUDY_CHAIR
References:
citation: 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.
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.
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.
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. doi: 10.3892/etm.2016.3676. Epub 2016 Sep 6.
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. doi: 10.1007/s13312-015-0677-z.
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.
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.
citation: 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.