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Patent Ductus Arteriosus After Premature BirthPhase 3IBUPARNCT04037514

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

A Phase 3 study testing Paracetamol and Ibuprofen in people with Patent Ductus Arteriosus After Premature Birth, run by Máximo Vento Torres at 4 sites in Spain.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages Up to 14 days
What is being tested?
Paracetamol and Ibuprofen
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
133 participants
Where
4 sitesSpain
Study dates
7 Jul 2017to 18 Dec 2024
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 14 days
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 14Show fewer
  • 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

Trial locations and contacts

4 sites in 1 country.

Spain4 sites
  • Hospital Reina Sofía

    Córdoba, Cordoba

  • Hospital Universitario de Cabueñes

    Gijón, Gijón

  • Hospital Materno-Infantil (Hospital Regional Carlos Haya) Málaga:

    Málaga, Málaga

  • Hospital Universitari i Politècnic La Fe

    Valencia, Valencia, 46026

Other trials in Spain

About this study

Official title: Paracetamol Versus Ibuprofen in Premature Infants With Hemodynamically Significant Patent Ductus Arteriosus: a Randomized Clinical Trial

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.

Read the 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.

Being tested
Paracetamol, Ibuprofen

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ParacetamolDrug

    Intravenous paracetamol 15 mg/kg/6h

  • IbuprofenDrug

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

Study groups in NCT04037514
Study groupRoleWhat they receive
ParacetamolExperimentalIntravenous paracetamol 15 mg/kg/6h for 3 or 6 days
Receives: Drug: Paracetamol
IbuprofenActive comparatorIntravenous ibuprofen 10 mg/kg/24 h (day 1) and 5 mg/kg/24h (day 2 and 3) for 3 or 6 days
Receives: Drug: Ibuprofen

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 24-48 hours after the completion of study intervention

Secondary outcomes (16)
  1. Need for a second course of treatment

    Measured: from randomization until discharge, an average of 2 months

  2. Closure rate after two treatment courses

    Measured: from randomization until discharge, an average of 2 months

  3. Need for rescue treatment after two courses of treatment

    Measured: from randomization until discharge, an average of 2 months

  4. Reopening rate after closure

    Measured: from randomization until discharge, an average of 2 months

  5. Closing rate after reopening

    Measured: from randomization until discharge, an average of 2 months

  6. Time required until closing

    Measured: from randomization until discharge, an average of 2 months

  7. Need for surgical ligation

    Measured: from randomization until discharge, an average of 2 months

  8. Incidence of early complications

    oliguria, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, hyperbilirubinemia, gastrointestinal bleeding or perforation

    Measured: from randomization until discharge, an average of 2 months

  9. Incidence of late complications

    bronchopulmonary dysplasia, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of the newborn, neurodevelopmental assessment, sepsis, death

    Measured: from randomization until 2 years

  10. Pharmacodynamics model of paracetamol in the context of hsPDA: Maximum Plasma Concentration [Cmax]

    Relation of effectiveness/adverse reactions to serum levels

    Measured: 24-48 hours after the completion of study intervention

  11. Pharmacodynamics model of paracetamol in the context of hsPDA: Minimum Plasma Concentration [Cmin]

    Relation of effectiveness/adverse reactions to serum levels

    Measured: 24-48 hours after the completion of study intervention

  12. Pharmacodynamics model of paracetamol in the context of hsPDA: Area Under the Curve [AUC])

    Relation of effectiveness/adverse reactions to serum levels

    Measured: 24-48 hours after the completion of study intervention

  13. Pharmacodynamics model of paracetamol in the context of hsPDA: urine metabolites

    Quantification of metabolites in urine and its relationship with drug elimination/metabolism

    Measured: 24-48 hours after the completion of study intervention

  14. Pharmacogenetics of paracetamol

    Genetic polymorphisms in TFAP2B, TGFBR2, EPAS1, MD-2 and GM2A genes related to efficacy/occurrence of adverse reactions

    Measured: 24-48 hours after the completion of study intervention

  15. Price-effectiveness ratio. Cost-effectiveness analysis depending on the efficiency obtained in the treatment.

    Measured: from randomization until discharge, an average of 2 months

  16. Genotoxicity mesured by %DNA damage

    Measured: from randomization until discharge, an average of 2 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Jul 2019
  2. Study start7 Jul 2017
  3. Primary completion18 Dec 2024
  4. Study completion18 Dec 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
133 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04037514
Sponsor's protocol ID
IBUPAR-TRIAL
Acronym
IBUPAR
Status last verified
Dec 2025
First submitted
23 Jul 2019
Last updated
18 Dec 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

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.

    PubMed 24223740
  • 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.

    PubMed 22065264
  • 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.

    PubMed 24359938
  • 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.

    PubMed 27698754
  • 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.

    PubMed 26244949
  • 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.

    PubMed 25471090
  • 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.

    PubMed 24941212
  • 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.

    PubMed 32766181

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Paracetamol and Ibuprofen in people with Patent Ductus Arteriosus After Premature Birth, run by Máximo Vento Torres at 4 sites in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04037514, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Dec 2025.

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