Paracetamol (Acetaminophen) for Closure of PDA in Preterm Infants

• ClinicalTrials.gov Identifier: NCT01755728
• Recruitment Status: Completed
• First Posted: December 24, 2012
• Last Update Posted: August 6, 2019
• Sponsor: Hillel Yaffe Medical Center
• Information provided by (Responsible Party): Erez Nadir, MD, Hillel Yaffe Medical Center

Tracking Information

• First Submitted Date: December 16, 2012
• First Posted Date: December 24, 2012
• Last Update Posted Date: August 6, 2019
• Actual Study Start Date: January 1, 2013
• Actual Primary Completion Date: December 31, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 19, 2012)

Closure of arterial duct - yes / No [ Time Frame: 1 week ]

Echo-cardiogram that will give exact answer to the question: "was the arterial duct closed"?

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 19, 2012)

Need for surgical closure of arterial duct [ Time Frame: 1 week ]

The clinical state of the infant will guide the team to ask the parents and the chest surgeon to surgically close the arterial duct

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: December 19, 2012)

Death or deterioration [ Time Frame: 1 week ]

The infant state deteriorates so quickly that it will die, either because of complication of the arterial duct, or because other causes, such as sepsis, metabolic disorder, etc...

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Paracetamol (Acetaminophen) for Closure of PDA in Preterm Infants
• Official Title: Paracetamol (Acetaminophen) for Closure of PDA in Preterm Infants

Brief Summary

There is a report that acetaminophen may have a role in pharmacological closure of PDA (Patent arterial duct) in preterm infants.

The investigators conducted this open label non randomized and non control study to try to support that report.

Detailed Description

In-uteri, the arterial duct connects between the aorta and the main pulmonary artery, thus bypassing the lungs. Since the high pulmonary pressure and the low systemic pressure, the shunt trough the arterial duct in that time is right to left.

After birth, systemic pressure rises and pulmonary pressure declines. As oxygen saturation rises, and prostaglandin secretion, the arterial duct closes, usually. In preterm infants, the arterial duct may remain open after birth. At this tume the shunt would be left to right, that would cause pulmonary congestion, and systemic hypoperfusion.

Ibuprofen is the treatment of choice for PDA in preterm infants. Yet, ibuprofen is not effective after two weeks of age. Moreover, there are situations that prevent treatment with ibuprofen, such as thrombocytopenia or renal failure. Surgical closure of arterial duct is an alternative treatment, if ibuprofen is contraindicated, or if it fails.

Lastly, there was a report that acetaminophen may have a role in pharmacological closure of PDA in preterm infants.

The investigators conducted this open label non randomized and non control study to try to support that report.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: PDA

Intervention

• Drug: Paracetamol
  Per gavage paracetamol 15 mg/kg every 6 hours, for up to 7 days.
  Other Name: Acetaminophen
• Drug: Ibuprofen
  Per Gavage ibuprofen 10mg/kg x 3/d for up to 5 days Gold standard per literature
• Procedure: Closure of PDA
  Open surgery for closure of PDA

Study Arms

• No Intervention: No known PDA
  For all infants, we do echo cardiogram study only if they are suspected of having PDA, due to sings and symptoms. Hence, we do not do echo cardiogram study to most of the infants.
• Active Comparator: Ibuprofen
  If there is a PDA, that should be treated, and the infant is less than 2 weeks of age, we use ibuprofen, as this is the gold standard in literature.
  Intervention: Drug: Ibuprofen
• Active Comparator: Surgical closure of PDA
  Infants with symptomatic PDA, who had to be treated, but could not be treated by ibuprofen, either due to age (> 2 weeks) or due ibuprofen contraindications (thrombocytopenia or renal failure), whose could not be treated by paracetamol (either because of parents' refuse or because they were on nothing per os protocol due to other disease), for whom surgery was the treatment of choice to close the arterial duct.
  Intervention: Procedure: Closure of PDA
• Experimental: Paracetamol
  Infants with symptomatic PDA who could not be treated with ibuprofen, and their parents agreed and they could be treated with paracetamol.
  Intervention: Drug: Paracetamol
• No Intervention: DA closed spontaneously
  Infants with PDA, who did not get any treatment for it, and the duct was closed spontaneously.

Publications *

• 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.
• Hammerman C, Bin-Nun A, Kaplan M. Managing the patent ductus arteriosus in the premature neonate: a new look at what we thought we knew. Semin Perinatol. 2012 Apr;36(2):130-8. doi: 10.1053/j.semperi.2011.09.023. Review.
• 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.
• Peterson RG. Consequences associated with nonnarcotic analgesics in the fetus and newborn. Fed Proc. 1985 Apr;44(7):2309-13. Review.
• Rudolph AM. Effects of aspirin and acetaminophen in pregnancy and in the newborn. Arch Intern Med. 1981 Feb 23;141(3 Spec No):358-63.
• Simbi KA, Secchieri S, Rinaldo M, Demi M, Zanardo V. In utero ductal closure following near-term maternal self-medication with nimesulide and acetaminophen. J Obstet Gynaecol. 2002 Jul;22(4):440-1.
• Weintraub A, Mankuta D. Dipyrone-induced oligohydramnios and ductus arteriosus restriction. Isr Med Assoc J. 2006 Oct;8(10):722-3.
• Burdan F, Starosławska E, Szumiło J. Prenatal tolerability of acetaminophen and other over-the-counter non-selective cyclooxygenase inhibitors. Pharmacol Rep. 2012;64(3):521-7. Review.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 5, 2019): 19
• Original Estimated Enrollment (submitted: December 19, 2012): 20
• Actual Study Completion Date: December 31, 2018
• Actual Primary Completion Date: December 31, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Preterm infants with symptomatic PDA who could not be treated with ibuprofen

Exclusion Criteria:

• None

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 4 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Israel

Administrative Information

• NCT Number: NCT01755728
• Other Study ID Numbers: 77-12-HYMC-CTIL
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Erez Nadir, MD, Hillel Yaffe Medical Center
• Study Sponsor: Hillel Yaffe Medical Center
• Collaborators: Not Provided

Investigators

• Principal Investigator: Erez Nadir, MD; Hillel Yaffe medical center, Hadera, Israel

• PRS Account: Hillel Yaffe Medical Center
• Verification Date: August 2019