- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03103022
Combination of Acetaminophen and Ibuprofen in the Management of Patent Ductus Arteriosus
Combination of Acetaminophen and Ibuprofen in the Management of Patent Ductus Arteriosus in Premature Infants: A Pilot Study
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The ductus arteriosus is an essential blood vessel that connects the pulmonary artery and the aorta in the fetus. The patent ductus arteriosus (PDA) allows oxygenated blood that returns from the placenta to bypass the lungs and supply the fetal systemic circulation. In fetal life, ductus remains open due to low partial pressure of oxygen, circulating or locally produced prostaglandins and local nitric oxide production. Constriction of ductal vascular smooth muscle (functional closure) occurs within few hours of delivery due to decrease level of prostaglandin and rising oxygen concentrations. Closure of ductus can be affected by several perinatal and postnatal factors such as growth restriction, sepsis, and fluid overload. Spontaneous PDA closure occurs in > 34% extreme premature infants compared to > 95% in infants with birth weight more than 1500 grams. In a prospective study, 65 infants less than 1500 g birth weight were closely followed by serial echocardiograms. Sensitivity of ductal tissue to oxygen and prostaglandin differs in preterm compared to term infants. Without sufficient physiologic hypoxia, the ductus may fail to close or may reopen after initial constriction. Several co-morbidities have been associated with prolonged patency of the ductus in preterm infants (e.g., prolonged ventilator support, bronchopulmonary dysplasia, pulmonary hemorrhage, impaired renal function, intraventricular hemorrhage and cerebral palsy). Preterm infants with uncomplicated respiratory course, PDA is commonly managed conservatively. Currently hemodynamically significant PDA are managed medically (indomethacin and ibuprofen) and surgically. Recently, acetaminophen has gained attention as an alternative for PDA management due to its low cost, wide availability and the potential for fewer side effects. In two randomized controlled trials comparing acetaminophen with ibuprofen, authors have shown comparable closure rate of PDA with acetaminophen.
To our knowledge, a combination of the drugs has not been used to treat PDA in preterm infants and prospective study has not been conducted or published to determine the effectiveness of a combination of ibuprofen and acetaminophen in the treatment of PDA. As both medications are metabolized through different organs (hepatic and renal), the investigator assume that incidence of adverse events should not be affected. The Investigator hypothesize that the combination of oral ibuprofen and oral acetaminophen will be more effective, because the mechanisms of action differ for the two medications and hence may produce therapeutic synergy.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Florida
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Jacksonville, Florida, United States, 32209
- University of Florida
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Jacksonville, Florida, United States, 32207
- Wolfson Children's Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Infant with gestational age 23 to 30 weeks at birth and birth weight between 500 - 1000 grams
- Postnatal age less than equal to 14 days
Hemodynamically significant PDA as defined by any of the following:
- Increased ventilator support attributed by the clinician to be due to PDA
- Hypotension and/or widening pulse pressure requiring vasopressors
- Signs of congestive heart failure such as pulmonary congestion
Echocardiographic criteria:
- Ratio of the smallest ductal diameter to the ostium of the left pulmonary artery > 0.5
Exclusion Criteria:
- PDA-dependent congenital heart disease
- Prior treatment with prophylactic indomethacin
- Significant hyperbilirubinemia requiring exchange transfusion
- Active or suspected necrotizing enterocolitis (NEC) and/or intestinal perforation
- Abnormal liver enzymes
- Platelets count < 50000 /l and / or active intracranial or gastrointestinal bleeding or from any other site
- Major congenital anomalies such as neural tube defect, chromosomal abnormality and gastrointestinal defect
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Interventional Group
Preterm infants who met the eligibility criteria will receive both oral acetaminophen and ibuprofen.
Oral acetaminophen [160 mg/5ml concentration] will be administered every 6 hours with dose of 15 mg/kg/dose for a total of twelve doses and oral ibuprofen [100 mg/5 ml] at 10 mg/kg/dose on first day followed by 5 mg/kg/dose at 24 and 48 hours for a total of three doses
|
Oral acetaminophen [160 mg/5ml concentration] will be administered every 6 hours with dose of 15 mg/kg/dose for a total of twelve doses
Other Names:
Oral ibuprofen [100 mg/5 ml] at 10 mg/kg/dose on first day followed by 5 mg/kg/dose at 24 and 48 hours for a total of three doses
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Ductal closing rate
Time Frame: within 24-48 hrs after completion of treatment.
|
To determine the ductal closure rate on echocardiography after completion of a first treatment course.
|
within 24-48 hrs after completion of treatment.
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Rate of ductal reopening
Time Frame: From birth until discharge / 36 weeks post menstrual age
|
Echocardiographic evidence of closure followed by later re-opening of ductus if further echocardiogram is indicated.
|
From birth until discharge / 36 weeks post menstrual age
|
Neonatal outcomes - Sepsis
Time Frame: until discharge / 36 weeks post menstrual age
|
late-onset sepsis duration of hospital stay and death.
Late onset sepsis: Defined as clinical signs of sepsis associated with a positive blood culture after 3 days of age.
|
until discharge / 36 weeks post menstrual age
|
Neonatal outcomes - Necrotizing Enterocolitis
Time Frame: until discharge / 36 weeks post menstrual age
|
Necrotizing Enterocolitis (NEC): defined as stage 2 or greater duration of hospital stay and death.
|
until discharge / 36 weeks post menstrual age
|
Neonatal outcomes - Bronchopulmonary Dysplasia
Time Frame: until discharge / 36 weeks post menstrual age
|
Late-onset bronchopulmonary dysplasia (BPD) is defined as oxygen requirement at 36 weeks or discharge for less than 32 weeks gestational infants duration of hospital stay and death.
|
until discharge / 36 weeks post menstrual age
|
neonatal outcomes - Ventilator days
Time Frame: until discharge / 36 weeks post menstrual age
|
The number of days that ventilator support is needed during hospitalization.
|
until discharge / 36 weeks post menstrual age
|
Neonatal outcomes- Intraventricular Hemorrhage
Time Frame: until discharge / 36 weeks post menstrual age
|
Late-onset severe intraventricular hemorrhage (IVH): IVH grade 3 and 4 both duration of hospital stay and death.
|
until discharge / 36 weeks post menstrual age
|
Neonatal outcomes - Periventricular Leukomalacia
Time Frame: until discharge / 36 weeks post menstrual age
|
late-onset periventricular leukomalacia information will be derived from routine head ultra sounds (US) at 36 weeks / discharge as a standard of care duration of hospital stay and death.
|
until discharge / 36 weeks post menstrual age
|
Neonatal outcomes - Retinopathy of Prematurity
Time Frame: until discharge / 36 weeks post menstrual age
|
Retinopathy of prematurity (ROP): severity of ROP will be derived from eye examination by pediatric ophthalmologist duration of hospital stay and death
|
until discharge / 36 weeks post menstrual age
|
Nutritional status - Weight
Time Frame: until discharge / 36 weeks post menstrual age
|
Weight in grams at birth and discharge or 36 weeks post menstrual age converted to percentile or Z score by using Fenton 2013 growth chart.
|
until discharge / 36 weeks post menstrual age
|
Nutritional status - Length
Time Frame: until discharge / 36 weeks post menstrual age
|
length in centimeters (cm) at birth and discharge or 36 weeks post menstrual age converted to either percentile or Z score by using Fenton 2013 growth chart.
|
until discharge / 36 weeks post menstrual age
|
Nutritional status - Head Circumference
Time Frame: until discharge / 36 weeks post menstrual age
|
Head circumference (HC) in cm at birth and discharge or 36 weeks post menstrual age converted to either percentile or Z score by using Fenton 2013 growth chart.
|
until discharge / 36 weeks post menstrual age
|
Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- El-Mashad AE, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr. 2017 Feb;176(2):233-240. doi: 10.1007/s00431-016-2830-7. Epub 2016 Dec 21.
- Prescott S, Keim-Malpass J. Patent Ductus Arteriosus in the Preterm Infant: Diagnostic and Treatment Options. Adv Neonatal Care. 2017 Feb;17(1):10-18. doi: 10.1097/ANC.0000000000000340.
- Coceani F, Baragatti B. Mechanisms for ductus arteriosus closure. Semin Perinatol. 2012 Apr;36(2):92-7. doi: 10.1053/j.semperi.2011.09.018.
- Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR. Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics. 2006 Apr;117(4):1113-21. doi: 10.1542/peds.2005-1528.
- Nemerofsky SL, Parravicini E, Bateman D, Kleinman C, Polin RA, Lorenz JM. The ductus arteriosus rarely requires treatment in infants > 1000 grams. Am J Perinatol. 2008 Nov;25(10):661-6. doi: 10.1055/s-0028-1090594. Epub 2008 Oct 10.
- Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? J Perinatol. 2010 Apr;30(4):241-52. doi: 10.1038/jp.2010.3. Epub 2010 Feb 25.
- 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.
- 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. Erratum In: J Pediatr. 2012 Jan;160(1):181.
- Olgun H, Ceviz N, Kartal I, Caner I, Karacan M, Tastekin A, Becit N. Repeated Courses of Oral Ibuprofen in Premature Infants with Patent Ductus Arteriosus: Efficacy and Safety. Pediatr Neonatol. 2017 Feb;58(1):29-35. doi: 10.1016/j.pedneo.2015.04.017. Epub 2016 Apr 29.
- Adamska E, Helwich E, Rutkowska M, Zacharska E, Piotrowska A. [Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants]. Med Wieku Rozwoj. 2005 Jul-Sep;9(3 Pt 1):335-54. Polish.
- Erdeve O, Yurttutan S, Altug N, Ozdemir R, Gokmen T, Dilmen U, Oguz SS, Uras N. Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2012 Jul;97(4):F279-83. doi: 10.1136/archdischild-2011-300532. Epub 2011 Dec 5.
- Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2011 Jul 6;(7):CD004213. doi: 10.1002/14651858.CD004213.pub3.
- Neumann R, Schulzke SM, Buhrer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. Neonatology. 2012;102(1):9-15. doi: 10.1159/000335332. Epub 2012 Mar 8.
- 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. No abstract available.
- 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.
- Yurttutan S, Oncel MY, Arayici S, Uras N, Altug N, Erdeve O, Dilmen U. A different first-choice drug in the medical management of patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med. 2013 May;26(8):825-7. doi: 10.3109/14767058.2012.755162. Epub 2013 Jan 15.
- Peterson RG. Consequences associated with nonnarcotic analgesics in the fetus and newborn. Fed Proc. 1985 Apr;44(7):2309-13.
- Terrin G, Conte F, Scipione A, Bacchio E, Conti MG, Ferro R, Ventriglia F, De Curtis M. Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm neonates. Ital J Pediatr. 2014 Feb 20;40(1):21. doi: 10.1186/1824-7288-40-21.
- Green K, Drvota V, Vesterqvist O. Pronounced reduction of in vivo prostacyclin synthesis in humans by acetaminophen (paracetamol). Prostaglandins. 1989 Mar;37(3):311-5. doi: 10.1016/0090-6980(89)90001-4.
- Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Paediatr Anaesth. 2008 Oct;18(10):915-21. doi: 10.1111/j.1460-9592.2008.02764.x.
- 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.
- Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, Canpolat FE, Dilmen U. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr. 2014 Mar;164(3):510-4.e1. doi: 10.1016/j.jpeds.2013.11.008. Epub 2013 Dec 18.
- Le J, Gales MA, Gales BJ. Acetaminophen for patent ductus arteriosus. Ann Pharmacother. 2015 Feb;49(2):241-6. doi: 10.1177/1060028014557564. Epub 2014 Oct 28.
- Tekgunduz KS, Ceviz N, Demirelli Y, Olgun H, Caner I, Sahin IO, Yolcu C. Intravenous paracetamol for patent ductus arteriosus in premature infants - a lower dose is also effective. Concerning the article by M.Y. Oncel et al: Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants [Neonatology 2013;103:166-169]. Neonatology. 2013;104(1):6-7. doi: 10.1159/000348568. Epub 2013 Mar 26. No abstract available.
- Oncel MY, Erdeve O. Oral medications regarding their safety and efficacy in the management of patent ductus arteriosus. World J Clin Pediatr. 2016 Feb 8;5(1):75-81. doi: 10.5409/wjcp.v5.i1.75. eCollection 2016 Feb 8.
- Romagnoli C, De Carolis MP, Papacci P, Polimeni V, Luciano R, Piersigilli F, Delogu AB, Tortorolo G. Effects of prophylactic ibuprofen on cerebral and renal hemodynamics in very preterm neonates. Clin Pharmacol Ther. 2000 Jun;67(6):676-83. doi: 10.1067/mcp.2000.107048.
- Peng S, Duggan A. Gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs. Expert Opin Drug Saf. 2005 Mar;4(2):157-69. doi: 10.1517/14740338.4.2.157.
- Kessel I, Waisman D, Lavie-Nevo K, Golzman M, Lorber A, Rotschild A. Paracetamol effectiveness, safety and blood level monitoring during patent ductus arteriosus closure: a case series. J Matern Fetal Neonatal Med. 2014 Nov;27(16):1719-21. doi: 10.3109/14767058.2013.871630. Epub 2014 Feb 7.
- Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am. 1986 Feb;33(1):179-201. doi: 10.1016/s0031-3955(16)34975-6.
- Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978 Apr;92(4):529-34. doi: 10.1016/s0022-3476(78)80282-0.
- Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr. 2013 Apr 20;13:59. doi: 10.1186/1471-2431-13-59.
- Ramos FG, Rosenfeld CR, Roy L, Koch J, Ramaciotti C. Echocardiographic predictors of symptomatic patent ductus arteriosus in extremely-low-birth-weight preterm neonates. J Perinatol. 2010 Aug;30(8):535-9. doi: 10.1038/jp.2010.14. Epub 2010 Feb 25.
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ACTUAL)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
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
- IRB201601912 - Jax
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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