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

Primary Purpose

Patent Ductus Arteriosus, Neonate

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Acetaminophen

ibuprofen

About this trial

This is an interventional treatment trial for Patent Ductus Arteriosus

Eligibility Criteria

23 Weeks - 30 Weeks (Child)All SexesDoes not accept healthy volunteers

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:
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
Echocardiographic criteria:
1. 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

Sites / Locations

Wolfson Children's Hospital
University of Florida

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Interventional Group

Arm Description

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

Outcomes

Primary Outcome Measures

Ductal closing rate

To determine the ductal closure rate on echocardiography after completion of a first treatment course.

Secondary Outcome Measures

Rate of ductal reopening

Echocardiographic evidence of closure followed by later re-opening of ductus if further echocardiogram is indicated.

Neonatal outcomes - Sepsis

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

Necrotizing Enterocolitis (NEC): defined as stage 2 or greater duration of hospital stay and death.

Neonatal outcomes - Bronchopulmonary Dysplasia

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

The number of days that ventilator support is needed during hospitalization.

Neonatal outcomes- Intraventricular Hemorrhage

Late-onset severe intraventricular hemorrhage (IVH): IVH grade 3 and 4 both duration of hospital stay and death.

Neonatal outcomes - Periventricular Leukomalacia

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

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

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

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

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.

Full Information

NCT ID

NCT03103022

First Posted

March 31, 2017

Last Updated

January 29, 2020

Sponsor

University of Florida

1. Study Identification

Unique Protocol Identification Number

NCT03103022

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2020

Overall Recruitment Status

Completed

Study Start Date

June 12, 2017 (Actual)

Primary Completion Date

April 30, 2019 (Actual)

Study Completion Date

April 30, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Florida

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Patent Ductus Arteriosus, Neonate

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Interventional Group

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Acetaminophen

Other Intervention Name(s)

Tylenol

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

ibuprofen

Other Intervention Name(s)

Motrin

Intervention Description

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

Primary Outcome Measure Information:

Title

Ductal closing rate

Description

To determine the ductal closure rate on echocardiography after completion of a first treatment course.

Time Frame

within 24-48 hrs after completion of treatment.

Secondary Outcome Measure Information:

Title

Rate of ductal reopening

Description

Echocardiographic evidence of closure followed by later re-opening of ductus if further echocardiogram is indicated.

Time Frame

From birth until discharge / 36 weeks post menstrual age

Title

Neonatal outcomes - Sepsis

Description

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.

Time Frame