Acetaminophen vs Indomethacin in Treating hsPDA

Patent Ductus Arteriosus Clinical Trial

Official title:

Comparison of the Efficacy of IV Acetaminophen Versus IV Indomethacin in Treatment of Hemodynamically Significant PDA in VLBW Infants

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03537144
• Other study ID #: 16-04411-FB
• Status: Terminated
• Phase: Phase 3
• Start date: June 2016
• Est. completion date: September 2018

Study information

• Verified date: May 2018
• Source: University of Tennessee
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to see if acetaminophen (Tylenol) is as effective as indomethacin in closing patent ductus arteriosus in premature infants.

Description:

The study will be a randomized, controlled, non-inferiority trial, and the investigators plan to enroll premature infants <32 weeks, <1500g, and who are < 21 days of age at Regional One Health, LeBonheur Children's Hospital, and Methodist Germantown NICUs in Memphis, TN. A study group of 42 patients for each group will be needed to allow a maximum difference of 25% to consider non-inferiority in the closure rate between IV acetaminophen and IV indomethacin (with power of 80% and alpha of 0.05).2 The investigators' goal will be to enroll 50 infants for each treatment group, to help with an expected 20% drop out rate either due to complications or parents removal of consent. Dosages: IV acetaminophen 15mg/kg/dose every 6 hours for 12 doses,6 IV indomethacin dose will depend on age.IV indomethacin will be given every 12 hours for 3 doses. The infants will be eligible for the study after primary attending has made the decision to treat the hsPDA. The goal will be 50 infants in the IV acetaminophen group and 50 infants in the IV indomethacin group.

Informed consent will be obtained from the parent after ECHO has been obtained and the primary attending has decided to treat PDA in the infant who meets inclusion criteria without any of the exclusion criteria. The investigators will use block randomization and stratify by site to generate 140 random values of either 0 for acetaminophen or 1 for indomethacin. The goal will be 50 infants randomized to acetaminophen group and 50 infants randomized to indomethacin group. The numbers will be placed in opaque envelope and opened after consent is obtained. The primary team will not be blinded given the different frequencies of administration of acetaminophen and indomethacin. The first ECHO will be read by staff pediatric cardiologist. A pediatric cardiologist will retrospectively go back and read all ECHOs blinded for standardization.

Prior to induction of treatment, we will record complete blood count (CBC) and complete metabolic panel (CMP) with AST/ALT. After treatment, the investigators will record AST/ALT within 48 hours, and will record follow-up ECHO reports that occur within seven days of initiation of treatment. The decision to repeat treatment will be left to primary attending's discretion. The primary attending will determine any additional medical or surgical treatment if indicated. Data regarding ROP, IVH, and BPD will be collected from patient's chart prior to discharge.

Primary outcome will be the rate of successful PDA treatment by ECHO in each group. Successful PDA treatment will be defined as no longer meeting ECHO criteria for hsPDA. Secondary outcome data will be recorded and include the following: retreatment, surgical closure, days on invasive mechanical ventilation, duration of supplemental oxygen requirement, respiratory support at 36 weeks post-menstrual age (PMA), NEC, ROP, days to full feeds, gastrointestinal perforation, length of stay, renal dysfunction defined by UOP < 1cc/kg/hr in an 8 hour period, creatinine elevation greater than 1.5 mg/dL, and discharge disposition.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 37
• Est. completion date: September 2018
• Est. primary completion date: September 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 22 Weeks to 32 Weeks

Eligibility

Inclusion Criteria:

• Gestational age at birth 22 weeks to 31 6/7 weeks.

• Birth weight = 1500 grams

• Day of life = 21 days

• ECHO findings:

Left-to-right ductal flow AND 2 of the following 3:

• Ductal size > 1.5mm at smallest diameter

• Reversal of flow in descending aorta

• Left atrial size to aortic root ratio >1.5

• Platelet count > 50,000

Exclusion Criteria:

• Ductal dependent congenital heart disease

• Major congenital anomaly

• Life-threatening infection

• Urine output < 1cc/kg/hr in prior 8 hours

• Serum creatinine > 1.8 mg/dL

• Hyperbilirubinemia requiring exchange transfusion

• Active NEC Stage 2 or 3 using Bell's staging criteria

• Active intestinal perforation

• Liver dysfunction [2x upper limit of normal for aspartate aminotransferase(AST) and/or alanine aminotransferase (ALT)]

• Active GI bleeding

• Concurrent hydrocortisone use

• Known IVH Grade 3 or 4

Related Conditions & MeSH terms

• Ductus Arteriosus, Patent
• Patent Ductus Arteriosus

Intervention

Drug:
• Indomethacin
IV indomethacin will be given every 12 hours for 3 doses. If <48 hours old, 1st dose 0.2 mg/kg, 2nd dose 0.1 mg/kg, and 3rd dose 0.1mg/kg. If 2-7 days old, 1st dose 0.2 mg/kg, 2nd dose 0.2 mg/kg, and 3rd dose 0.2 mg/kg. If >7 days old, 1st dose 0.2 mg/kg, 2nd dose 0.25 mg/kg, and 3rd dose 0.25 mg/kg.
• Acetaminophen
15mg/kg/dose every 6 hours for 12 doses

Locations

Country	Name	City	State
United States	LeBonheur Children's Hospital	Memphis	Tennessee
United States	Methodist-Lebonheur Germantown Hospital	Memphis	Tennessee
United States	Regional One Health	Memphis	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
University of Tennessee

Country where clinical trial is conducted

United States, 

References & Publications (18)

Benitz WE; Committee on Fetus and Newborn, American Academy of Pediatrics. Patent Ductus Arteriosus in Preterm Infants. Pediatrics. 2016 Jan;137(1). doi: 10.1542/peds.2015-3730. Epub 2015 Dec 15. — View Citation

Clyman, R. Patent Ductus Arteriosus in the Preterm Infant. in: C.A. Gleason, SU Devaskar (Eds.) Avery's disease of the newborn.9th ed.WB Saunders, Philadelphia;2012:751-761.

Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLoS One. 2013 Nov 4;8(11):e77888. doi: 10.1371/journal.pone.0077888. eCollec — View Citation

Dash SK, Kabra NS, Avasthi BS, Sharma SR, Padhi P, Ahmed J. Enteral paracetamol or Intravenous Indomethacin for Closure of Patent Ductus Arteriosus in Preterm Neonates: A Randomized Controlled Trial. Indian Pediatr. 2015 Jul;52(7):573-8. — View Citation

EL-Khuffash A, James AT, Cleary A, Semberova J, Franklin O, Miletin J. Late medical therapy of patent ductus arteriosus using intravenous paracetamol. Arch Dis Child Fetal Neonatal Ed. 2015 May;100(3):F253-6. doi: 10.1136/archdischild-2014-307930. Epub 20 — View Citation

Ellison RC, Peckham GJ, Lang P, Talner NS, Lerer TJ, Lin L, Dooley KJ, Nadas AS. Evaluation of the preterm infant for patent ductus arteriosus. Pediatrics. 1983 Mar;71(3):364-72. — View Citation

Evans N, Malcolm G, Osborn D, Kluckow M. Diagnosis of patent ductus arteriosus in preterm infants. Neonatal Rev 2004; 5: e86-e97.

Gersony WM, Peckham GJ, Ellison RC, Miettinen OS, Nadas AS. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr. 1983 Jun;102(6):895-906. — View Citation

Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr. 2011 Apr;158(4):549-554.e1. doi: 10.1016/j.jpeds.2010.10.00 — View 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. — View Citation

Jain A, Shah PS. Diagnosis, Evaluation, and Management of Patent Ductus Arteriosus in Preterm Neonates. JAMA Pediatr. 2015 Sep;169(9):863-72. doi: 10.1001/jamapediatrics.2015.0987. Review. — View Citation

Martin, R. J., Fanaroff, A. A., & Walsh, M. C. (2015). Fanaroff and Martin's neonatal-perinatal medicine: Diseases of the fetus and infant (10th ed.). St. Louis, Mo.: Mosby/Elsevier

Nadir E, Kassem E, Foldi S, Hochberg A, Feldman M. Paracetamol treatment of patent ductus arteriosus in preterm infants. J Perinatol. 2014 Oct;34(10):748-9. doi: 10.1038/jp.2014.96. Epub 2014 May 22. — View 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. Ep — View Citation

Palmer GM, Atkins M, Anderson BJ, Smith KR, Culnane TJ, McNally CM, Perkins EJ, Chalkiadis GA, Hunt RW. I.V. acetaminophen pharmacokinetics in neonates after multiple doses. Br J Anaesth. 2008 Oct;101(4):523-30. doi: 10.1093/bja/aen208. Epub 2008 Jul 15. — View Citation

Silverman NH, Lewis AB, Heymann MA, Rudolph AM. Echocardiographic assessment of ductus arteriosus shunt in premature infants. Circulation. 1974 Oct;50(4):821-5. — View Citation

Terrin G, Conte F, Oncel MY, Scipione A, McNamara PJ, Simons S, Sinha R, Erdeve O, Tekgunduz KS, Dogan M, Kessel I, Hammerman C, Nadir E, Yurttutan S, Jasani B, Alan S, Manguso F, De Curtis M. Paracetamol for the treatment of patent ductus arteriosus in p — View Citation

Thomson Reuters. Neofax 2011. Montvale, NJ: Thomson Reuters; 2011.

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Successful treatment of PDA closure	Definition of successful treatment of PDA is the PDA no longer meets the echocardiogram inclusion criteria.	Follow-up ECHO to assess for closure within 7 days of treatment initiation
Secondary	PDA retreatment	Did the patient require a second course of treatment with either indomethacin or acetaminophen. Did the PDA require surgical closure.	1 year
Secondary	Supplement O2 requirement at 36 weeks PMA	Was infant on >21% O2 at 36 weeks post-menstrual age	Until 36 weeks PMA
Secondary	Nectrotizing enterocolitis	As defined by Bell's Staging criteria, at any time during hospital stay	1 year
Secondary	Gastrointestinal perforation	As defined by xray demonstration of free peritoneal air or as diagnosed by surgery	1 year
Secondary	Mortality	Death before discharge from NICU stay	1 year
Secondary	Days on invasive mechanical ventilation	Days on invasive mechanical ventilation	1 year
Secondary	Days on supplement oxygen	Days on supplement oxygen	1 year
Secondary	Days to full feeds	Day till the infant reaches 120 kcal/kg/d	1 year
Secondary	Length of stay	Time from NICU admission to NICU discharge	1 year
Secondary	Retinopathy of prematurity	Stage of ROP and if any treatment was needed	1 year
Secondary	Creatinine elevation greater than 1.5 mg/dL	Creatinine elevation greater than 1.5 mg/dL	1 year