Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus (IBUPAR)
Primary Purpose
Patent Ductus Arteriosus After Premature Birth
Status
Unknown status
Phase
Phase 3
Locations
Spain
Study Type
Interventional
Intervention
Paracetamol
Ibuprofen
Sponsored by
About this trial
This is an interventional treatment trial for Patent Ductus Arteriosus After Premature Birth
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
Sites / Locations
- Hospital Reina SofíaRecruiting
- Hospital Universitario de Cabueñes
- Hospital Materno-Infantil (Hospital Regional Carlos Haya) Málaga:Recruiting
- Hospital Universitari i Politècnic La FeRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Paracetamol
Ibuprofen
Arm Description
Intravenous paracetamol 15 mg/kg/6h for 3 or 6 days
Intravenous ibuprofen 10 mg/kg/24 h (day 1) and 5 mg/kg/24h (day 2 and 3) for 3 or 6 days
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Need for a second course of treatment
Closure rate after two treatment courses
Need for rescue treatment after two courses of treatment
Reopening rate after closure
Closing rate after reopening
Time required until closing
Need for surgical ligation
Incidence of early complications
oliguria, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, hyperbilirubinemia, gastrointestinal bleeding or perforation
Incidence of late complications
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]
Relation of effectiveness/adverse reactions to serum levels
Pharmacodynamics model of paracetamol in the context of hsPDA: Minimum Plasma Concentration [Cmin]
Relation of effectiveness/adverse reactions to serum levels
Pharmacodynamics model of paracetamol in the context of hsPDA: Area Under the Curve [AUC])
Relation of effectiveness/adverse reactions to serum levels
Pharmacodynamics model of paracetamol in the context of hsPDA: urine metabolites
Quantification of metabolites in urine and its relationship with drug elimination/metabolism
Pharmacogenetics of paracetamol
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.
Genotoxicity mesured by %DNA damage
Full Information
NCT ID
NCT04037514
First Posted
July 23, 2019
Last Updated
July 26, 2019
Sponsor
Máximo Vento Torres
Collaborators
Instituto de Investigacion Sanitaria La Fe, Spanish Clinical Research Network - SCReN
1. Study Identification
Unique Protocol Identification Number
NCT04037514
Brief Title
Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus
Acronym
IBUPAR
Official Title
Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus: a Randomized Clinical Trial
Study Type
Interventional
2. Study Status
Record Verification Date
July 2019
Overall Recruitment Status
Unknown status
Study Start Date
July 7, 2017 (Actual)
Primary Completion Date
January 31, 2020 (Anticipated)
Study Completion Date
February 28, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Máximo Vento Torres
Collaborators
Instituto de Investigacion Sanitaria La Fe, Spanish Clinical Research Network - SCReN
4. Oversight
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
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Patent Ductus Arteriosus After Premature Birth
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
300 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Paracetamol
Arm Type
Experimental
Arm Description
Intravenous paracetamol 15 mg/kg/6h for 3 or 6 days
Arm Title
Ibuprofen
Arm Type
Active Comparator
Arm Description
Intravenous ibuprofen 10 mg/kg/24 h (day 1) and 5 mg/kg/24h (day 2 and 3) for 3 or 6 days
Intervention Type
Drug
Intervention Name(s)
Paracetamol
Intervention Description
Intravenous paracetamol 15 mg/kg/6h
Intervention Type
Drug
Intervention Name(s)
Ibuprofen
Intervention Description
Intravenous ibuprofen 10 mg/kg/24h (day 1) and 5 mg/kg/24h (day 2 and 3)
Primary Outcome Measure Information:
Title
Rate of closure of the hsPDA after treatment with paracetamol (experimental drug) versus ibuprofen (control drug).
Description
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.
Time Frame
24-48 hours after the completion of study intervention
Secondary Outcome Measure Information:
Title
Need for a second course of treatment
Time Frame
from randomization until discharge, an average of 2 months
Title
Closure rate after two treatment courses
Time Frame
from randomization until discharge, an average of 2 months
Title
Need for rescue treatment after two courses of treatment
Time Frame
from randomization until discharge, an average of 2 months
Title
Reopening rate after closure
Time Frame
from randomization until discharge, an average of 2 months
Title
Closing rate after reopening
Time Frame
from randomization until discharge, an average of 2 months
Title
Time required until closing
Time Frame
from randomization until discharge, an average of 2 months
Title
Need for surgical ligation
Time Frame
from randomization until discharge, an average of 2 months
Title
Incidence of early complications
Description
oliguria, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, hyperbilirubinemia, gastrointestinal bleeding or perforation
Time Frame
from randomization until discharge, an average of 2 months
Title
Incidence of late complications
Description
bronchopulmonary dysplasia, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of the newborn, neurodevelopmental assessment, sepsis, death
Time Frame
from randomization until 2 years
Title
Pharmacodynamics model of paracetamol in the context of hsPDA: Maximum Plasma Concentration [Cmax]
Description
Relation of effectiveness/adverse reactions to serum levels
Time Frame
24-48 hours after the completion of study intervention
Title
Pharmacodynamics model of paracetamol in the context of hsPDA: Minimum Plasma Concentration [Cmin]
Description
Relation of effectiveness/adverse reactions to serum levels
Time Frame
24-48 hours after the completion of study intervention
Title
Pharmacodynamics model of paracetamol in the context of hsPDA: Area Under the Curve [AUC])
Description
Relation of effectiveness/adverse reactions to serum levels
Time Frame
24-48 hours after the completion of study intervention
Title
Pharmacodynamics model of paracetamol in the context of hsPDA: urine metabolites
Description
Quantification of metabolites in urine and its relationship with drug elimination/metabolism
Time Frame
24-48 hours after the completion of study intervention
Title
Pharmacogenetics of paracetamol
Description
Genetic polymorphisms in TFAP2B, TGFBR2, EPAS1, MD-2 and GM2A genes related to efficacy/occurrence of adverse reactions
Time Frame
24-48 hours after the completion of study intervention
Title
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
Title
Genotoxicity mesured by %DNA damage
Time Frame
from randomization until discharge, an average of 2 months
10. Eligibility
Sex
All
Maximum Age & Unit of Time
14 Days
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marta Aguar Carrascosa, PhD, MD
Phone
0034 961245686
Email
maraca@alumni.uv.es
First Name & Middle Initial & Last Name or Official Title & Degree
Ana García Robles, PharmD
Phone
0034 961245686
Email
garcia.anarob@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Maximo Vento Torres, PhD, MD
Organizational Affiliation
Hospital Universitario La Fe
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Reina Sofía
City
Córdoba
State/Province
Cordoba
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
María José Párraga Quiles, MD
Email
majopaqui@yahoo.es
Facility Name
Hospital Universitario de Cabueñes
City
Gijón
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marta Costa Romero, MD
Email
marta.costar78@gmail.com
Facility Name
Hospital Materno-Infantil (Hospital Regional Carlos Haya) Málaga:
City
Málaga
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maria del Mar Serrano Martín, MD
Email
mmarser@live.com
Facility Name
Hospital Universitari i Politècnic La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marta Aguar Carrasacosa, PhD, MD
Email
maraca@alumni.uv.es
First Name & Middle Initial & Last Name & Degree
Ana García Robles, PharmD
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
24223740
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.
Results Reference
background
PubMed Identifier
22065264
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.
Results Reference
background
PubMed Identifier
24359938
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.
Results Reference
background
PubMed Identifier
27698754
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.
Results Reference
background
PubMed Identifier
26244949
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.
Results Reference
background
PubMed Identifier
25471090
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.
Results Reference
background
PubMed Identifier
24941212
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.
Results Reference
background
PubMed Identifier
32766181
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. Erratum In: Front Pediatr. 2022 Jan 13;9:834454.
Results Reference
derived
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Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus
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