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

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ClinicalTrials.gov Identifier: NCT04037514
Recruitment Status : Recruiting
First Posted : July 30, 2019
Last Update Posted : July 30, 2019
Sponsor:
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  ICMJE July 23, 2019
First Posted Date  ICMJE July 30, 2019
Last Update Posted Date July 30, 2019
Actual Study Start Date  ICMJE July 7, 2017
Estimated Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Patent Ductus Arteriosus After Premature Birth
Intervention  ICMJE
  • 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  ICMJE
  • 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 *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 26, 2019)
300
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 28, 2022
Estimated Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 14 Days   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04037514
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Máximo Vento Torres, Instituto de Investigacion Sanitaria La Fe
Study Sponsor  ICMJE Máximo Vento Torres
Collaborators  ICMJE
  • Instituto de Investigacion Sanitaria La Fe
  • Spanish Clinical Research Network - CAIBER
Investigators  ICMJE
Study Chair: Maximo Vento Torres, PhD, MD Hospital Universitario La Fe
PRS Account Instituto de Investigacion Sanitaria La Fe
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP