Randomized Controlled Trial to Evaluate the Safety and Efficacy of Acetaminophen in Preterm Infants Used in Combination With Ibuprofen for Closure of the Ductus Arteriosus

Single Center, Randomized, Double Blind, Placebo Controlled Trial to Evaluate the Safety and Efficacy of Acetaminophen in Preterm Infants Used in Combination With Ibuprofen for Closure of the Ductus Arteriosus

The purpose of the present study is to determine whether treatment of hemodynamically significant patent ductus arteriosus with a combined therapy of intravenous Ibuprofen and oral acetaminophen has higher success rate in closing the ductus arteriosus than a standard treatment strategy of using intravenous ibuprofen alone among preterm infants.

Study Overview

• Status: Terminated
• Conditions: Bronchopulmonary Dysplasia; Patent Ductus Arteriosus; Preterm Infant
• Intervention / Treatment: Drug: Ibuprofen and acetaminophen; Drug: Ibuprofen and placebo

Detailed Description

The primary objectives of the study are to confirm the safety of oral acetaminophen in extremely low birth infants, given concomitantly with intravenous ibuprofen and also to determine its efficacy in significantly increasing the rates of ductal closure when compared to only intravenous ibuprofen therapy. Hence primary outcome variable include patent ductus arteriosus closure success rate, based on the 2-D transthoracic echocardiographic evidence.

This study is a single center, randomized, double blinded, placebo controlled trial. Preterm infants with gestational age of with a gestational age ≤27 6/7 weeks by the best obstetric estimate are eligible for enrollment.

For randomization, the study population will be stratified to two subgroups based on gestational age (GA ≤24 weeks and > 25 weeks). Randomization will occur by using computer generated random sequence, using a 4-block design, with 1:1 parallel allocation. Allocations include treatment and control arm. Treatment arm will receive combination of intravenous ibuprofen and oral acetaminophen, while control arm will receive intravenous Ibuprofen and oral placebo.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36607
      • University of South Alabama

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 days to 3 weeks (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Preterm infant ≤27 6/7
2. Written parental consent is obtained
3. Infant requires respiratory support

4. diagnosis of a persistent patent ductus arteriosus after 5 days of age, (defined as at least two of the following:

   1. Ductus size ≥ 1.5 mm
   2. Maximum flow velocity through the ductus ≤ 2 m/s
   3. Left atrium to aorta ratio ≥ 1.4
   4. Wide pulse pressure
   5. B-type natriuretic peptide (BNP)
5. Attending neonatologist made decision to treat patent ductus arteriosus

Exclusion Criteria:

1. No parental consent
2. Infants > 21days of postnatal age
3. Congenital anomalies such as cardiac or multiple anomalies
4. Infection (e.g., septicemia, pneumonia)
5. Bleeding disorder or platelet count< 50,000/ml
6. Acute kidney injury (AKI)defined as oliguria (urine output< 0.5 ml/kg/hr for 16hrs) and/or serum creatinine > 1.5 mg/dl
7. Elevated liver enzymes (>2 fold from upper normal limits)
8. Pulmonary hypertension or right to left shunt through the ductus arteriosus
9. Diagnosis of necrotizing enterocolitis
10. Unable to tolerate oral medications at the time of enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ibuprofen and acetaminophen arm (intervention arm); ibuprofen and acetaminophen will be administered concomitantly. Ibuprofen will be administered through intravenous route. The dose of ibuprofen will be the standard dosing regimen used in our unit: dosing based on the postnatal age. For Infants > 108 h of postnatal age: 18 mg/kg/dose loading dose followed by 9 mg/kg/dose, two doses at q24 intervals, started 24 h after the loading dose. Acetaminophen will be administered as oral formulation. Acetaminophen is given at a dose of 15 mg/Kg/dose, q 6 hours, for 3 days (total of 12 doses).	Drug: Ibuprofen and acetaminophen; Intravenous ibuprofen given concomitantly with oral acetaminophen
Active Comparator: ibuprofen and placebo arm (control arm); ibuprofen and acetaminophen will be administered concomitantly. Ibuprofen will be administered through intravenous route. The dose of ibuprofen will be the standard dosing regimen used in our unit: dosing based on the postnatal age. For Infants > 108 h of postnatal age: 18 mg/kg/dose loading dose followed by 9 mg/kg/dose, two doses at q24 intervals, started 24 h after the loading dose. Placebo will be sterile water, with similar volume and color as acetaminophen, will be given through the oro-gastric tube, for three days at 6 h intervals.	Drug: Ibuprofen and placebo; Intravenous ibuprofen given concomitantly with oral placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With Ductus Arteriosus Closure/Constriction	Ductal closure/constriction rate as defined based on the echocardiographic findings. Ductal closure/constriction will be defined as the complete closure of ductus or ductal diameter <1 mm	24-48 hours after the completion of study intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Echocardiographic Patent Ductus Arteriosus Parameters Before and After the Study Intervention	Echocardiographic parameters including ductal size (PDA size in mm), Left atrium to aortic root ratio, ductal velocity, descending aortic diastolic flow, before and after the intervention. Between the group and within the group comparison	24-48 hours after the completion of study intervention
Ventilatory Settings Before and After the Study Intervention	Ventilator parameters including Fio2, Mean airway pressure, Peak Inspiratory pressure, PEEP, and ventilatory rate oxygenation indices including Oxygenation index and Respiratory Severity score before and after intervention	24-48 hours after the completion of study intervention
Proportion of Participants With Liver Injury	liver enzymes compared before and after the study intervention; if any significant elevation of liver enzymes from baseline, the participant classified as having liver injury	24-48 hours after the completion of study intervention
Proportion of Participants With Renal Injury	Blood urea nitrogen (BUN) and serum creatinine before and after the study intervention are compared. Participants exhibiting significant elevation BUN and S creatine, are classified as having renal injury	24-48 hours after the completion of study intervention
Proportion of Participants With Hematological Adverse Events	Hematocrit and platelet counts compared before and after the study intervention; if any significant alteration from baseline, the participant classified as having hematological adverse event,	24-48 hours after the completion of study intervention
Total Number of Days of Mechanical Ventilation	The total number of days on mechanical ventilation are counted as total duration of conventional mechanical ventilation plus high frequency ventilatory days	from randomization until discharge/40 weeks post menstrual age
Total Number of Days of Need for Supplemental Oxygen	Cumulative days on any supplemental O2 (including Mechanical ventilation., noninvasive ventilation, nasal cannula support) calculated from randomization until 4 weeks of postmenstrual age	from randomization until discharge/40 weeks post menstrual age
Duration of Noninvasive Ventilation	Total cumulative days on noninvasive ventilation, including NIPPV and nasal CPAP,	from randomization until discharge/40 weeks post menstrual age
Proportion of Participants With Persistence of Ductus-needing Pharmacological Treatment	Proportion of participants in each group requiring open label treatment with pharmacological agents for ductal closure, e.g. IV Ibuprofen or IV Acetaminophen or IV indomethacin therapies, as decided by the treating physician	from randomization until discharge/40 weeks post menstrual age
Proportion of Participants Requiring Surgical Ligation of PDA	Proportion of participants in each group requiring surgical ligation of persistent PDA for definitive surgical closure	from randomization until discharge/40 weeks post menstrual age
Proportion of Participants Developing Bronchopulmonary Dysplasia	Proportion of participants diagnosed to have BPD based supplemental O2 requirement at 36 weeks' postmenstrual age	at 36 weeks post menstrual age
Percentage of Infants Requiring Home Oxygen Therapy	Proportion of participants in each group requiring home-based supplemental O2 therapy following the initial discharge from hospital.	at discharge/40 weeks post menstrual age
Proportion of Participants Developing Death Before Discharge	Proportion of participants in each group developing in-hospital death prior to 40 weeks of postmenstrual age.	until discharge/40 weeks post menstrual age
Time to Achieve Full Enteral Feeding	Duration days during the postnatal period required to achieve an enteral feeding volume of 120 ml/kg/day.	from birth until discharge/40 weeks post menstrual age
Total Days on Total Parenteral Nutrition	Cumulative days of receiving total parental nutrition from birth until the participant is discharged or reached postmenstrual age of 40 weeks	from birth until discharge/40 weeks post menstrual age
Proportion of Participants With Retinopathy of Prematurity	Proportion of participants in each group diagnosed to have retinopathy of prematurity	from birth until discharge/40 weeks post menstrual age
Proportion of Participants Developing Spontaneous Intestinal Perforation	Proportion of participants developing or having the diagnosis of spontaneous intestinal perforation from randomization until discharge or 40 weeks' Postmenstrual age	from randomization until discharge/40 weeks post menstrual age
Proportion of Participants Developing Necrotizing Enterocolitis	Proportion of participants in each group with the diagnosis of medical or surgical Necrotizing Enterocolitis	from randomization until discharge/40 weeks post menstrual age
Proportion of Participants Developing Gastrointestinal Hemorrhage	Proportion of participants in each group developing gastrointestinal hemorrhage following randomization until discharge or postmenstrual age of 40 weeks	from randomization until discharge/40 weeks post menstrual age
Proportion of Participants Developing Late Onset Sepsis	Proportion of participants diagnosed to have either probable sepsis with minimum of 7 days of antibiotic therapy or culture proven sepsis	from randomization until discharge/40 weeks post menstrual age
Length of Hospital Stay	Total duration (in days ) of hospital stay	from birth until discharge/40 weeks post menstrual age
Proportion of Participants With Periventricular Leukomalacia	Proportion of participants in each group with the evidence of periventricular leukomalacia on neurosonography	from randomization until discharge/40 weeks post menstrual age

Collaborators and Investigators

• Sponsor: University of South Alabama
• Investigators: Study Director: Fabien Eyal, MD, University of South Alabama

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2018
• Primary Completion (Actual): October 30, 2020
• Study Completion (Actual): December 2, 2020

Study Registration Dates

• First Submitted: August 22, 2018
• First Submitted That Met QC Criteria: October 5, 2018
• First Posted (Actual): October 9, 2018

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: mechanical ventilation; acetaminophen; ibuprofen; bronchopulmonary dysplasia; patent ductus arteriosus
• Additional Relevant MeSH Terms: Urogenital Diseases; Cardiovascular Diseases; Female Urogenital Diseases and Pregnancy Complications; Heart Diseases; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Respiratory Tract Diseases; Lung Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Lung Injury; Ventilator-Induced Lung Injury; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Premature Birth; Ductus Arteriosus, Patent; Bronchopulmonary Dysplasia; Organic Chemicals; Carboxylic Acids; Anilides; Amides; Aniline Compounds; Amines; Acetanilides; Acids, Carbocyclic; Phenylpropionates; Acetaminophen; Ibuprofen
• Other Study ID Numbers: 15-081/730216-8

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No