Acetaminophen vs Indomethacin in Treating hsPDA

NCT ID: NCT03537144

Last Updated: 2019-12-03

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE3

Total Enrollment

37 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-06-30

Study Completion Date

2018-09-30

Brief Summary

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

Detailed Description

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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.

Conditions

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Patent Ductus Arteriosus

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Outcome Assessors

Study Groups

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Indomethacin

Indomethacin as drug to treat PDA.

Group Type ACTIVE_COMPARATOR

Indomethacin

Intervention Type DRUG

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

Acetaminophen as drug to treat PDA.

Group Type EXPERIMENTAL

Acetaminophen

Intervention Type DRUG

15mg/kg/dose every 6 hours for 12 doses

Interventions

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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.

Intervention Type DRUG

Acetaminophen

15mg/kg/dose every 6 hours for 12 doses

Intervention Type DRUG

Other Intervention Names

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Indocin Ofirmev

Eligibility Criteria

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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
Minimum Eligible Age

22 Weeks

Maximum Eligible Age

32 Weeks

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Tennessee

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Locations

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LeBonheur Children's Hospital

Memphis, Tennessee, United States

Site Status

Methodist-Lebonheur Germantown Hospital

Memphis, Tennessee, United States

Site Status

Regional One Health

Memphis, Tennessee, United States

Site Status

Countries

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United States

References

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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.

Reference Type RESULT
PMID: 22065264 (View on PubMed)

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. eCollection 2013.

Reference Type RESULT
PMID: 24223740 (View on PubMed)

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.

Reference Type RESULT
PMID: 24854626 (View on PubMed)

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.

Reference Type RESULT
PMID: 26168357 (View on PubMed)

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. Epub 2012 Dec 19.

Reference Type RESULT
PMID: 23258386 (View on PubMed)

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 2015 Feb 4.

Reference Type RESULT
PMID: 25653299 (View on PubMed)

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.2010.10.008. Epub 2010 Nov 20.

Reference Type RESULT
PMID: 21094951 (View on PubMed)

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

Reference Type RESULT

Silverman NH, Lewis AB, Heymann MA, Rudolph AM. Echocardiographic assessment of ductus arteriosus shunt in premature infants. Circulation. 1974 Oct;50(4):821-5. doi: 10.1161/01.cir.50.4.821. No abstract available.

Reference Type RESULT
PMID: 4418268 (View on PubMed)

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.

Reference Type RESULT
PMID: 6338474 (View on PubMed)

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. doi: 10.1007/s13312-015-0677-z.

Reference Type RESULT
PMID: 26244949 (View on PubMed)

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

Reference Type RESULT

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

Reference Type RESULT

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.

Reference Type RESULT

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 preterm neonates: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2016 Mar;101(2):F127-36. doi: 10.1136/archdischild-2014-307312. Epub 2015 Aug 17.

Reference Type RESULT
PMID: 26283668 (View on PubMed)

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.

Reference Type RESULT
PMID: 18628265 (View on PubMed)

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.

Reference Type RESULT
PMID: 26672023 (View on PubMed)

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. doi: 10.1016/s0022-3476(83)80022-5.

Reference Type RESULT
PMID: 6343572 (View on PubMed)

Other Identifiers

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16-04411-FB

Identifier Type: -

Identifier Source: org_study_id

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