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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 : June 24, 2019
Sponsor:
Information provided by (Responsible Party):
University of Florida

Study Description
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Brief Summary:
Patent ductus arteriosus or PDA is a blood vessel that connects the right and left side of the heart that usually closes after birth but remains open in some premature infants born before 30 weeks' gestation. When this blood vessel remains open for a long time, it may cause problems such as bleeding in the lung and brain, lung injury due to prolonged need of ventilator, and poor kidney function. It sometimes becomes necessary to close this blood vessel in the preterm infant. Currently, this blood vessel can be closed either by medication or surgery. Pain medications such as Ibuprofen and Indomethacin are routinely used medications to close PDA. However, in the last 5 year, acetaminophen has been found as an alternative medication to close PDA in preterm infants. In multiple studies, acetaminophen is found to be a safe alternative medication with lower side effects than current standard management. Intravenous Ibuprofen is approved by FDA to treat PDA in preterm infants. Although not approved by FDA, oral ibuprofen is being used for the management of PDA. However, the success rate of a single medication is approximately 70%. Both medications have been used in the previous clinical studies to treat the same condition in the preterm infants and fewer side effects were reported. Mechanism of both medications to close PDA is different and may work more effectively together than single medication alone. In this study, the investigator are going to use these two medications (Ibuprofen and Acetaminophen) at the same time if the child needs treatment and is eligible to participate in this study. This study is based on the assumption that by using both medications at the same time, investigator can close this blood vessel more effectively than with either drug alone.

Condition or disease Intervention/treatment Phase
Patent Ductus Arteriosus Neonate Drug: Acetaminophen Drug: ibuprofen Phase 1

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
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

Resource links provided by the National Library of Medicine


Arms and Interventions
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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
 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


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. neonatal outcomes - Ventilator days [ Time Frame: until discharge / 36 weeks post menstrual age ]
    The number of days that ventilator support is needed during hospitalization.

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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.


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

Inclusion Criteria:

  1. Infant with gestational age 23 to 30 weeks at birth and birth weight between 500 - 1000 grams
  2. Postnatal age less than equal to 14 days

  3. Hemodynamically significant PDA as defined by any of the following:

    1. Increased ventilator support attributed by the clinician to be due to PDA
    2. Hypotension and/or widening pulse pressure requiring vasopressors
    3. Signs of congestive heart failure such as pulmonary congestion

  4. Echocardiographic criteria:

    1. Ratio of the smallest ductal diameter to the ostium of the left pulmonary artery > 0.5

Exclusion Criteria:

  1. PDA-dependent congenital heart disease
  2. Prior treatment with prophylactic indomethacin
  3. Significant hyperbilirubinemia requiring exchange transfusion
  4. Active or suspected necrotizing enterocolitis (NEC) and/or intestinal perforation
  5. Abnormal liver enzymes
  6. Platelets count < 50000 /l and / or active intracranial or gastrointestinal bleeding or from any other site
  7. Major congenital anomalies such as neural tube defect, chromosomal abnormality and gastrointestinal defect
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

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


Locations
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United States, Florida
Wolfson Children's Hospital
Jacksonville, Florida, United States, 32207
University of Florida
Jacksonville, Florida, United States, 32209
Sponsors and Collaborators
University of Florida
More Information
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Publications:

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03103022     History of Changes
Other Study ID Numbers: IRB201601912 - Jax
First Posted: April 6, 2017    Key Record Dates
Last Update Posted: June 24, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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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