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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

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.

Condition or disease Intervention/treatment Phase
Patent Ductus Arteriosus After Premature Birth Drug: Paracetamol Drug: Ibuprofen Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus: a Randomized Clinical Trial
Actual Study Start Date : July 7, 2017
Estimated Primary Completion Date : January 31, 2020
Estimated Study Completion Date : February 28, 2022


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

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
Drug: Ibuprofen
Intravenous ibuprofen 10 mg/kg/24h (day 1) and 5 mg/kg/24h (day 2 and 3)




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Need for a second course of treatment [ Time Frame: from randomization until discharge, an average of 2 months ]
  2. Closure rate after two treatment courses [ Time Frame: from randomization until discharge, an average of 2 months ]
  3. Need for rescue treatment after two courses of treatment [ Time Frame: from randomization until discharge, an average of 2 months ]
  4. Reopening rate after closure [ Time Frame: from randomization until discharge, an average of 2 months ]
  5. Closing rate after reopening [ Time Frame: from randomization until discharge, an average of 2 months ]
  6. Time required until closing [ Time Frame: from randomization until discharge, an average of 2 months ]
  7. Need for surgical ligation [ Time Frame: from randomization until discharge, an average of 2 months ]
  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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 ]
  16. Genotoxicity mesured by %DNA damage [ Time Frame: from randomization until discharge, an average of 2 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 14 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04037514


Contacts
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Contact: Marta Aguar Carrascosa, PhD, MD 0034 961245686 maraca@alumni.uv.es
Contact: Ana García Robles, PharmD 0034 961245686 garcia.anarob@gmail.com

Locations
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Spain
Hospital Reina Sofía Recruiting
Córdoba, Cordoba, Spain
Contact: María José Párraga Quiles, MD       majopaqui@yahoo.es   
Hospital Universitario de Cabueñes Not yet recruiting
Gijón, Spain
Contact: Marta Costa Romero, MD       marta.costar78@gmail.com   
Hospital Materno-Infantil (Hospital Regional Carlos Haya) Málaga: Recruiting
Málaga, Spain
Contact: Maria del Mar Serrano Martín, MD       mmarser@live.com   
Hospital Universitari i Politècnic La Fe Recruiting
Valencia, Spain, 46026
Contact: Marta Aguar Carrasacosa, PhD, MD       maraca@alumni.uv.es   
Sub-Investigator: Ana García Robles, PharmD         
Sponsors and Collaborators
Máximo Vento Torres
Instituto de Investigacion Sanitaria La Fe
Spanish Clinical Research Network - CAIBER
Investigators
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Study Chair: Maximo Vento Torres, PhD, MD Hospital Universitario La Fe

Publications:

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Responsible Party: Máximo Vento Torres, Scientific Director Health Research Institute La Fe, Instituto de Investigacion Sanitaria La Fe
ClinicalTrials.gov Identifier: NCT04037514     History of Changes
Other Study ID Numbers: IBUPAR-TRIAL
First Posted: July 30, 2019    Key Record Dates
Last Update Posted: July 30, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Ibuprofen
Premature Birth
Ductus Arteriosus, Patent
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities
Acetaminophen
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antipyretics