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Paracetamol in Patent Ductus Arteriosus

Primary Purpose

Ductus Arteriosus, Patent

Status

Completed

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

Paracetamol

Ibuprofen

About this trial

This is an interventional treatment trial for Ductus Arteriosus, Patent

Eligibility Criteria

25 Weeks - 31 Weeks (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female preterm infants with no limitation of race.
Gestational age 25(+0) - 31(+6) weeks.
Age 24-72 hours.
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.
Willingness of the parents/legally authorized representative/child to sign the Consent Informed Form.

Exclusion Criteria:

Outborn patients.
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.
Known positive HIV and/or known positive Hepatitis C Virus newborn's mother.
Life threatening infection, complicated or not by multiple organ dysfunction and failure syndrome.
Fetal hydrops.
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.
Grade 3 or 4 intraventricular haemorrhage (IVH).
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.
Serum creatinine concentration > 1.5 mg/dl (132 μmol/l).
Platelet count < 50,000/mm3.
Major bleeding, as revealed by hematuria, or blood in the endotracheal aspirate, gastric aspirate, or stools, or consistent oozing of blood from puncture sites.
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
Medical need of administering other Nonsteroidal Antiinflammatory Drug (NSAID) different from ibuprofen.
Participation to another trial involving any investigational drug.

Sites / Locations

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

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Paracetamol

Ibuprofen

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

success rate in closing PDA using paracetamol in comparison to ibuprofen.

assessed echocardiographically.

Secondary Outcome Measures

number of re-openings.

assessed echocardiographically.

success rate in closing PDA after the second treatment course of ibuprofen as rescue medication.

assessed echocardiographically.

success rate of closing PDA after the first day of the first treatment course.

assessed echocardiographically.

success rate of closing PDA after the second day of the first treatment course.

assessed echocardiographically.

incidence of surgical ligation.

incidence of renal failure, liver failure and gastrointestinal complications (including isolated intestinal perforation).

assessed by laboratory analysis.

incidence of death,

incidence of death.

incidence of sepsis.

hospital-stay duration in Neonatal Intensive Care Unit.

occurrence of adverse effects.

Full Information

NCT ID

NCT02422966

First Posted

April 9, 2015

Last Updated

July 11, 2019

Sponsor

Aziende Chimiche Riunite Angelini Francesco S.p.A

1. Study Identification

Unique Protocol Identification Number

NCT02422966

Brief Title

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

2. Study Status

Record Verification Date

July 2019

Overall Recruitment Status

Completed

Study Start Date

December 2015 (Actual)

Primary Completion Date

January 2019 (Actual)

Study Completion Date

April 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Aziende Chimiche Riunite Angelini Francesco S.p.A

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ductus Arteriosus, Patent

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

110 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Paracetamol

Arm Type

Experimental

Arm Description

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.

Arm Title

Ibuprofen

Arm Type

Active Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Paracetamol

Other Intervention Name(s)

Acetaminophen

Intervention Type

Drug

Intervention Name(s)

Ibuprofen

Primary Outcome Measure Information:

Title

success rate in closing PDA using paracetamol in comparison to ibuprofen.

Description

assessed echocardiographically.

Time Frame

at Visit 3 (day 3).

Secondary Outcome Measure Information:

Title

number of re-openings.

Description

assessed echocardiographically.

Time Frame

at Follow-up 3 (day 30).

Title

success rate in closing PDA after the second treatment course of ibuprofen as rescue medication.

Description

assessed echocardiographically.

Time Frame

at Visit 6 (day 6).

Title

success rate of closing PDA after the first day of the first treatment course.

Description

assessed echocardiographically.

Time Frame

at Visit 1 (day 1).

Title

success rate of closing PDA after the second day of the first treatment course.

Description

assessed echocardiographically.

Time Frame

at Visit 2 (day 2).

Title

incidence of surgical ligation.

Time Frame

at Follow-up 3 (day 30).

Title

incidence of renal failure, liver failure and gastrointestinal complications (including isolated intestinal perforation).

Description

assessed by laboratory analysis.

Time Frame

at Follow-up 3 (day 30).

Title

incidence of death,

Time Frame

at Follow-up 3 (day 30).

Title

incidence of death.

Time Frame

at Follow-up 4 (40 weeks post-conception).

Title

incidence of sepsis.

Time Frame

at Follow-up 3 (day 30).

Title

hospital-stay duration in Neonatal Intensive Care Unit.

Time Frame

at Follow-up 4 (40 weeks post-conception).

Title

occurrence of adverse effects.

Time Frame

at Follow-up 3 (day 30).

10. Eligibility

Sex

All

Minimum Age & Unit of Time

25 Weeks

Maximum Age & Unit of Time

31 Weeks

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female preterm infants with no limitation of race. Gestational age 25(+0) - 31(+6) weeks. Age 24-72 hours. 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. Willingness of the parents/legally authorized representative/child to sign the Consent Informed Form. Exclusion Criteria: Outborn patients. 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. Known positive HIV and/or known positive Hepatitis C Virus newborn's mother. Life threatening infection, complicated or not by multiple organ dysfunction and failure syndrome. Fetal hydrops. 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. Grade 3 or 4 intraventricular haemorrhage (IVH). 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. Serum creatinine concentration > 1.5 mg/dl (132 μmol/l). Platelet count < 50,000/mm3. Major bleeding, as revealed by hematuria, or blood in the endotracheal aspirate, gastric aspirate, or stools, or consistent oozing of blood from puncture sites. 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 Medical need of administering other Nonsteroidal Antiinflammatory Drug (NSAID) different from ibuprofen. Participation to another trial involving any investigational drug.

Facility Information:

Facility Name

Azienda Ospedaliero Universitaria Careggi - Neonatologia e Terapia Intensiva Neonatale

City

Firenze

ZIP/Postal Code

50134

Country

Italy

Facility Name

IRCCS "Giannina Gaslini" Genova - Patologia Neonatale e Terapia Intensiva Neonatale

City

Genova

ZIP/Postal Code

16147

Country

Italy

Facility Name

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico U.O. di Neonatologia e Terapia Intensiva Neonatale

City

Milano

ZIP/Postal Code

20122

Country

Italy

Facility Name

Azienda Ospedaliera Istituti Clinici di Perfezionamento (ICP) - Ospedale dei Bambini "Vittore Buzzi" Milano - Neonatologia

City

Milano

ZIP/Postal Code

20154

Country

Italy

Facility Name

Policlinico Gemelli Roma - UOC Neonatologia

City

Roma

ZIP/Postal Code

00168

Country

Italy

12. IPD Sharing Statement

Citations:

PubMed Identifier

32888085

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.

Results Reference

derived

PubMed Identifier

27038924

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.

Results Reference

derived

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Paracetamol in Patent Ductus Arteriosus

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