Paracetamol in Patent Ductus Arteriosus

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

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.

Study Overview

• Status: Completed
• Conditions: Ductus Arteriosus, Patent
• Intervention / Treatment: Drug: Paracetamol; Drug: Ibuprofen

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.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Firenze, Italy, 50134
    • Azienda Ospedaliero Universitaria Careggi - Neonatologia e Terapia Intensiva Neonatale
  • Genova, Italy, 16147
    • IRCCS "Giannina Gaslini" Genova - Patologia Neonatale e Terapia Intensiva Neonatale
  • Milano, Italy, 20122
    • Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico U.O. di Neonatologia e Terapia Intensiva Neonatale
  • Milano, Italy, 20154
    • Azienda Ospedaliera Istituti Clinici di Perfezionamento (ICP) - Ospedale dei Bambini "Vittore Buzzi" Milano - Neonatologia
  • Roma, Italy, 00168
    • Policlinico Gemelli Roma - UOC Neonatologia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 months to 8 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Paracetamol; Paracetamol intravenous solution 15 mg/kg (corresponding to 1.5 ml/kg) per dose every 6 hours for 3 days, for a total amount of 12 doses.	Drug: Paracetamol; Other Names: Acetaminophen
Active Comparator: Ibuprofen; Ibuprofen intravenous solution at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 5 mg/kg at 48 h.	Drug: Ibuprofen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
success rate in closing PDA using paracetamol in comparison to ibuprofen.	assessed echocardiographically.	at Visit 3 (day 3).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
number of re-openings.	assessed echocardiographically.	at Follow-up 3 (day 30).
success rate in closing PDA after the second treatment course of ibuprofen as rescue medication.	assessed echocardiographically.	at Visit 6 (day 6).
success rate of closing PDA after the first day of the first treatment course.	assessed echocardiographically.	at Visit 1 (day 1).
success rate of closing PDA after the second day of the first treatment course.	assessed echocardiographically.	at Visit 2 (day 2).
incidence of surgical ligation.		at Follow-up 3 (day 30).
incidence of renal failure, liver failure and gastrointestinal complications (including isolated intestinal perforation).	assessed by laboratory analysis.	at Follow-up 3 (day 30).
incidence of death,		at Follow-up 3 (day 30).
incidence of death.		at Follow-up 4 (40 weeks post-conception).
incidence of sepsis.		at Follow-up 3 (day 30).
hospital-stay duration in Neonatal Intensive Care Unit.		at Follow-up 4 (40 weeks post-conception).
occurrence of adverse effects.		at Follow-up 3 (day 30).

Collaborators and Investigators

• Sponsor: Aziende Chimiche Riunite Angelini Francesco S.p.A

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: April 9, 2015
• First Submitted That Met QC Criteria: April 17, 2015
• First Posted (Estimate): April 22, 2015

Study Record Updates

• Last Update Posted (Actual): July 12, 2019
• Last Update Submitted That Met QC Criteria: July 11, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Ductus Arteriosus, Patent; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antipyretics; Acetaminophen; Ibuprofen
• Other Study ID Numbers: 044CF13273