Combination of Acetaminophen and Ibuprofen in the Management of Patent Ductus Arteriosus

January 29, 2020 updated by: University of Florida

Combination of Acetaminophen and Ibuprofen in the Management of Patent Ductus Arteriosus in Premature Infants: A Pilot Study

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.

Study Overview

Status

Completed

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

Interventional

Enrollment (Actual)

20

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Florida
      • Jacksonville, Florida, United States, 32209
        • University of Florida
      • Jacksonville, Florida, United States, 32207
        • Wolfson Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

5 months to 6 months (CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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:
  • Tylenol
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:
  • Motrin

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

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 12, 2017

Primary Completion (ACTUAL)

April 30, 2019

Study Completion (ACTUAL)

April 30, 2019

Study Registration Dates

First Submitted

March 31, 2017

First Submitted That Met QC Criteria

March 31, 2017

First Posted (ACTUAL)

April 6, 2017

Study Record Updates

Last Update Posted (ACTUAL)

January 31, 2020

Last Update Submitted That Met QC Criteria

January 29, 2020

Last Verified

January 1, 2020

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

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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