Clinical trial NCT02422966: Paracetamol in Patent Ductus Arteriosus
Official title: Efficacy and Safety of Paracetamol in Comparison to Ibuprofen for Patent Ductus Arteriosus Treatment in Preterm Infants: A Randomized, Open Label, Comparator-controlled, Prospective Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ductus Arteriosus, Patent
Lead sponsor: Aziende Chimiche Riunite Angelini Francesco S.p.A
Sponsor class: INDUSTRY
First posted: 2015-04-22
Enrollment: 110
Sex: ALL
Minimum age (years): 25
Maximum age (years): 31
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to assess the efficacy and safety of paracetamol in comparison to ibuprofen in the treatment of patent ductus arteriosus (PDA) in preterm infants.

Detailed description: Although patency of the ductus arteriosus is essential for fetal circulation, the postnatal ductal closure is critical for postnatal circulatory adaptation. In premature infants the circulating prostaglandin levels are higher than at term, and respiratory difficulties may lead to a state of hypoxia, which contribute to the failure of the ductus closure. Recently, an incidental finding in one preterm infant led to look at paracetamol, one of the most common drugs available, as an alternative therapeutic approach to ductal closure. If paracetamol is proven to be effective, it could become the treatment of choice for the management of PDA, mainly due to its more favorable safety profile.

Although the recent results available in the literature demonstrates an highly success rate in ductal closure with paracetamol, all case studies are not powered to show efficacy of paracetamol for PDA closure. Further prospective randomized-controlled trials are needed to evaluate the efficacy of paracetamol versus ibuprofen for the closure of PDA.

If paracetamol is indeed proven to be effective, it could become the treatment of choice for the management of PDA, mainly due to its more favorable side effect profile. In order to test this hypothesis, a randomized, open label, parallel groups, comparator controlled, multicentre, prospective study is proposed.

Eligibility criteria: Inclusion Criteria:

1. Male or female preterm infants with no limitation of race.
2. Gestational age 25(+0) - 31(+6) weeks.
3. Age 24-72 hours.
4. Echocardiographic evidence of hemodynamically significant patent ductus arteriosus at the first 24-72 hours of life.

   The diagnosis of hemodynamically significant PDA requiring treatment will be made by echocardiographic demonstration of a ductal left-to-right shunt, with a left atrium-to-aortic root ratio \>1.3 or a ductal size \>1.5 mm and excluding the cases in which the closing flow pattern suggests a restrictive PDA.
5. Willingness of the parents/legally authorized representative/child to sign the Consent Informed Form.

Exclusion Criteria:

1. Outborn patients.
2. Major congenital anomalies, including but not limited to congenital heart defects, Down syndrome newborn and/or new born suffering from congenital anomalies diagnosed during the fetal period.
3. Known positive HIV and/or known positive Hepatitis C Virus newborn's mother.
4. Life threatening infection, complicated or not by multiple organ dysfunction and failure syndrome.
5. Fetal hydrops.
6. Pulmonary hypertension diagnosed in the first 24-48 hours of life by means of heart ultrasound when the presence of a right-to-left shunt through the foramen ovale or ductus arteriosus is demonstrated, or when the estimated pulmonary pressure, in terms of the tricuspid regurgitation jet, is greater than two-thirds of the systemic arterial pressure.
7. Grade 3 or 4 intraventricular haemorrhage (IVH).
8. Urine output \<1 ml/kg of body weight/h during a 24 h collection period or urine output \<0.5 ml/kg of body weight/h in case it is measured at 24 hours of life of newborn.
9. Serum creatinine concentration \> 1.5 mg/dl (132 μmol/l).
10. Platelet count \< 50,000/mm3.
11. Major bleeding, as revealed by hematuria, or blood in the endotracheal aspirate, gastric aspirate, or stools, or consistent oozing of blood from puncture sites.
12. Severe liver failure, defined as elevated liver enzymes (ALT/Glutamate-Pyruvate Transaminase and Aspartate aminotransferase/GOT) \> 2 times the upper boundary of the normal range. For this kind of population the following normal ranges will be considered \[Rosenthal, 1997\]:

    * ALT/Glutamate-pyruvate transaminase: 6-50 U/L
    * Aspartate aminotransferase/GOT: 35-140 U/L
13. Medical need of administering other Nonsteroidal Antiinflammatory Drug (NSAID) different from ibuprofen.
14. Participation to another trial involving any investigational drug.

Primary outcomes:
measure: success rate in closing PDA using paracetamol in comparison to ibuprofen.
timeFrame: at Visit 3 (day 3).
Secondary outcomes:
measure: number of re-openings.
timeFrame: at Follow-up 3 (day 30).
measure: success rate in closing PDA after the second treatment course of ibuprofen as rescue medication.
timeFrame: at Visit 6 (day 6).
measure: success rate of closing PDA after the first day of the first treatment course.
timeFrame: at Visit 1 (day 1).
measure: success rate of closing PDA after the second day of the first treatment course.
timeFrame: at Visit 2 (day 2).
measure: incidence of surgical ligation.
timeFrame: at Follow-up 3 (day 30).
measure: incidence of renal failure, liver failure and gastrointestinal complications (including isolated intestinal perforation).
timeFrame: at Follow-up 3 (day 30).
measure: incidence of death,
timeFrame: at Follow-up 3 (day 30).
measure: incidence of death.
timeFrame: at Follow-up 4 (40 weeks post-conception).
measure: incidence of sepsis.
timeFrame: at Follow-up 3 (day 30).
measure: hospital-stay duration in Neonatal Intensive Care Unit.
timeFrame: at Follow-up 4 (40 weeks post-conception).
measure: occurrence of adverse effects.
timeFrame: at Follow-up 3 (day 30).
Other outcomes:
Locations:
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi - Neonatologia e Terapia Intensiva Neonatale
city: Genova
country: Italy
facility: IRCCS "Giannina Gaslini" Genova - Patologia Neonatale e Terapia Intensiva Neonatale
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico U.O. di Neonatologia e Terapia Intensiva Neonatale
city: Milano
country: Italy
facility: Azienda Ospedaliera Istituti Clinici di Perfezionamento (ICP) - Ospedale dei Bambini "Vittore Buzzi" Milano - Neonatologia
city: Roma
country: Italy
facility: Policlinico Gemelli Roma - UOC Neonatologia
Study officials:
References:
citation: Dani C, Lista G, Bianchi S, Mosca F, Schena F, Ramenghi L, Zecca E, Vento G, Poggi C, Leonardi V, Minghetti D, Rosignoli MT, Calisti F, Comandini A, Cattaneo A, Lipone P. Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a randomized controlled trial. Eur J Pediatr. 2021 Mar;180(3):807-816. doi: 10.1007/s00431-020-03780-8. Epub 2020 Sep 4.
citation: Dani C, Poggi C, Mosca F, Schena F, Lista G, Ramenghi L, Romagnoli C, Salvatori E, Rosignoli MT, Lipone P, Comandini A. Efficacy and safety of intravenous paracetamol in comparison to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: study protocol for a randomized control trial. Trials. 2016 Apr 2;17:182. doi: 10.1186/s13063-016-1294-4.