Clinical trial NCT02056223: Paracetamol vs Ibuprofen for PDA Closure in Preterm Infants.
Official title: Paracetamol Versus Ibuprofen for Patent Ductus Arteriosus Closure in Preterm Infants. A Prospective, Randomized, Controlled, Double Blind, Multicenter Clinical Trial.
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
PHASE3
Conditions: Ductus Arteriosus Patent
Respiratory Distress Syndrome
Keywords: Patent ductus arteriosus
Preterm infant
Paracetamol
Ibuprofen
Lead sponsor: University of Padova
Sponsor class: OTHER
First posted: 2014-02-05
Enrollment: 120
Sex: ALL
Minimum age (years): 36
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Current pharmacological options to treat an hemodynamically significant PDA (HsPDA) in preterm infants are limited to non-selective cyclo-oxygenase (COX) inhibitors, indomethacin or ibuprofen. Recently paracetamol exposure has been reported to successful closure of PDA. Aim of this randomized double-blind controlled study is to compare the efficacy and the safety of standard PDA treatment ibuprofen versus paracetamol-experimental treatment . We hypothesize that paracetamol is more effective than ibuprofen in closing PDA, perhaps ameliorating the safety profile of the pharmacological treatment.

Detailed description: The objective of this trial is to compare the efficacy and safety of 2 therapeutic regimens for PDA treatment in a population of preterm newborns of gestational age (GA) \<31+6 weeks with respiratory distress syndrome (RDS) and HsPDA:

* Group A: experimental boluses of paracetamol at 15 mg/Kg four time a day for three consecutive days.
* Group B: standard boluses of ibuprofen at 10-5-5-mg/Kg/dose once a day for three consecutive days.

The primary objective of the study is: to evaluate the efficacy of paracetamol versus standard ibuprofen regimen, by comparing the rate of ductal closure after the first and second course of pharmacological treatment. (PDA diagnosed by ECHO criteria)

The secondary objective of the study is: to evaluate the safety of the above 2 therapeutic regimens in term of incidence of transient renal impairment, intraventricular hemorrhage (IVH) or other bleeding disorders, necrotizing enterocolitis (NEC) and isolated bowel perforation (without signs of NEC), incidence of sign of liver toxicity.

Eligibility criteria: Inclusion Criteria:

* inborn neonates
* preterm neonates ≤ 31+ 6 days weeks gestation
* newborns with HsPDA
* parental written informed consent for participation in the study must be obtained

Exclusion Criteria:

* Serum creatinine concentration greater than 1,5 mg/dl (132MMole/L)
* Urine output less than 1 ml/Kg/h
* Severe IVH (\> grade II according to Volpe classification)
* Clinical bleeding tendency (as revealed by hematuria, blood in the gastric aspirate or in the stools, blood in the endotracheal tube aspirate)
* Necrotizing enterocolitis or marked abdominal distention with gastric bile residuals
* Thrombocyte count of less than 50.000/mm3
* Proved Sepsis
* Severe coagulopathy or liver failure
* Evidence of severe birth asphyxia, that is an APGAR score below 5 at 5 minutes of age and/or umbilical arterial pH \< 7.0
* Known genetic or chromosomal disorders
* Participation in another clinical trial of any placebo, drug, biological, or device conducted under the provisions of a protocol.

Primary outcomes:
measure: PDA pharmacological closure
timeFrame: Partecipants will be evaluated at the end of first and second course, at an expected avarage of 8 days of life (DOL)
Secondary outcomes:
measure: Oliguria
timeFrame: In the first 14 days of life
Other outcomes:
measure: Necrotizing enterocolitis (NEC)
timeFrame: In the first 14 days of life
measure: Intraventricular haemorrhage (IVH) or death
timeFrame: Within 28 days of life
Locations:
city: Padua
country: Italy
facility: NICU, Women's and Children's Health Department, Azienda Ospedaliera-University of Padua
Study officials:
affiliation: Women's and Children's Health Department- AO- University of Padua
name: Paola Lago, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Oncel MY, Yurttutan S, Degirmencioglu H, Uras N, Altug N, Erdeve O, Dilmen U. Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology. 2013;103(3):166-9. doi: 10.1159/000345337. Epub 2012 Dec 19.
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.
citation: Oncel MY, Yurttutan S, Uras N, Altug N, Ozdemir R, Ekmen S, Erdeve O, Dilmen U. An alternative drug (paracetamol) in the management of patent ductus arteriosus in ibuprofen-resistant or contraindicated preterm infants. Arch Dis Child Fetal Neonatal Ed. 2013 Jan;98(1):F94. doi: 10.1136/archdischild-2012-302044. Epub 2012 May 18. No abstract available.
citation: Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child. 2011 Jun;96(6):575-80. doi: 10.1136/adc.2010.204552. Epub 2011 Feb 13.