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

• ClinicalTrials.gov Identifier: NCT04037514
• Recruitment Status: Recruiting
• First Posted: July 30, 2019
• Last Update Posted: July 30, 2019
• Sponsor: Máximo Vento Torres
• Collaborators: Instituto de Investigacion Sanitaria La Fe; Spanish Clinical Research Network - CAIBER
• Information provided by (Responsible Party): Máximo Vento Torres, Instituto de Investigacion Sanitaria La Fe

Tracking Information

• First Submitted Date: July 23, 2019
• First Posted Date: July 30, 2019
• Last Update Posted Date: July 30, 2019
• Actual Study Start Date: July 7, 2017
• Estimated Primary Completion Date: January 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 26, 2019)

Rate of closure of the hsPDA after treatment with paracetamol (experimental drug) versus ibuprofen (control drug). [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: July 26, 2019)

• Need for a second course of treatment [ Time Frame: from randomization until discharge, an average of 2 months ]
• Closure rate after two treatment courses [ Time Frame: from randomization until discharge, an average of 2 months ]
• Need for rescue treatment after two courses of treatment [ Time Frame: from randomization until discharge, an average of 2 months ]
• Reopening rate after closure [ Time Frame: from randomization until discharge, an average of 2 months ]
• Closing rate after reopening [ Time Frame: from randomization until discharge, an average of 2 months ]
• Time required until closing [ Time Frame: from randomization until discharge, an average of 2 months ]
• Need for surgical ligation [ Time Frame: from randomization until discharge, an average of 2 months ]
• Incidence of early complications [ Time Frame: from randomization until discharge, an average of 2 months ]
  oliguria, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, hyperbilirubinemia, gastrointestinal bleeding or perforation
• Incidence of late complications [ Time Frame: from randomization until 2 years ]
  bronchopulmonary dysplasia, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of the newborn, neurodevelopmental assessment, sepsis, death
• Pharmacodynamics model of paracetamol in the context of hsPDA: Maximum Plasma Concentration [Cmax] [ Time Frame: 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] [ Time Frame: 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]) [ Time Frame: 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 [ Time Frame: 24-48 hours after the completion of study intervention ]
  Quantification of metabolites in urine and its relationship with drug elimination/metabolism
• Pharmacogenetics of paracetamol [ Time Frame: 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. [ Time Frame: from randomization until discharge, an average of 2 months ]
• Genotoxicity mesured by %DNA damage [ Time Frame: from randomization until discharge, an average of 2 months ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Patent Ductus Arteriosus After Premature Birth

Intervention

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

Study Arms

• Experimental: Paracetamol
  Intravenous paracetamol 15 mg/kg/6h for 3 or 6 days
  Intervention: Drug: Paracetamol
• 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
  Intervention: Drug: Ibuprofen

Publications *

• 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.
• 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.
• 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. 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.
• 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.
• García-Robles A, Gimeno Navarro A, Serrano Martín MDM, Párraga Quiles MJ, Parra Llorca A, Poveda-Andrés 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 26, 2019): 300
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 28, 2022
• Estimated Primary Completion Date: January 31, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 14 Days (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Marta Aguar Carrascosa, PhD, MD; 0034 961245686; maraca@alumni.uv.es

Contact: Ana García Robles, PharmD; 0034 961245686; garcia.anarob@gmail.com

• Listed Location Countries: Spain

Administrative Information

• NCT Number: NCT04037514
• Other Study ID Numbers: IBUPAR-TRIAL
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Máximo Vento Torres, Instituto de Investigacion Sanitaria La Fe
• Study Sponsor: Máximo Vento Torres

Collaborators

• Instituto de Investigacion Sanitaria La Fe
• Spanish Clinical Research Network - CAIBER

Investigators

• Study Chair: Maximo Vento Torres, PhD, MD; Hospital Universitario La Fe

• PRS Account: Instituto de Investigacion Sanitaria La Fe
• Verification Date: July 2019