Combination of Acetaminophen and Ibuprofen in the Management of Patent Ductus Arteriosus
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ClinicalTrials.gov Identifier: NCT03103022 |
Recruitment Status :
Completed
First Posted : April 6, 2017
Last Update Posted : January 31, 2020
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Condition or disease | Intervention/treatment | Phase |
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Patent Ductus Arteriosus Neonate | Drug: Acetaminophen Drug: ibuprofen | Phase 1 |
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 : | Interventional (Clinical Trial) |
Actual Enrollment : | 20 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | Combination of Acetaminophen and Ibuprofen in the Management of Patent Ductus Arteriosus in Premature Infants: A Pilot Study |
Actual Study Start Date : | June 12, 2017 |
Actual Primary Completion Date : | April 30, 2019 |
Actual Study Completion Date : | April 30, 2019 |

Arm | Intervention/treatment |
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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
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Drug: Acetaminophen
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 Name: Tylenol Drug: ibuprofen 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 Name: Motrin |
- 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.
- 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.
- 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.
- 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.
- 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.
- neonatal outcomes - Ventilator days [ Time Frame: until discharge / 36 weeks post menstrual age ]The number of days that ventilator support is needed during hospitalization.
- 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.
- 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.
- 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
- 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.
- 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.
- 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.

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Ages Eligible for Study: | 23 Weeks to 30 Weeks (Child) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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
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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
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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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03103022
United States, Florida | |
Wolfson Children's Hospital | |
Jacksonville, Florida, United States, 32207 | |
University of Florida | |
Jacksonville, Florida, United States, 32209 |
Responsible Party: | University of Florida |
ClinicalTrials.gov Identifier: | NCT03103022 |
Other Study ID Numbers: |
IRB201601912 - Jax |
First Posted: | April 6, 2017 Key Record Dates |
Last Update Posted: | January 31, 2020 |
Last Verified: | January 2020 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Ductus Arteriosus, Patent Heart Defects, Congenital Cardiovascular Abnormalities Cardiovascular Diseases Heart Diseases Congenital Abnormalities Acetaminophen Ibuprofen Analgesics, Non-Narcotic Analgesics |
Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Antipyretics Anti-Inflammatory Agents, Non-Steroidal Anti-Inflammatory Agents Antirheumatic Agents Cyclooxygenase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |