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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Patent Ductus Arteriosus, Preterm Infant, Bronchopulmonary Dysplasia

Intervention / Treatment
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* Drug: Ibuprofen and acetaminophen
* Drug: Ibuprofen and placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Preterm infant ≤27 6/7 Written parental consent is obtained Infant requires respiratory support diagnosis of a persistent patent ductus arteriosus after 5 days of age, (defined as at least two of the following: Ductus size ≥ 1.5 mm Maximum flow velocity through the ductus ≤ 2 m/s Left atrium to aorta ratio ≥ 1.4 Wide pulse pressure B-type natriuretic peptide (BNP) Attending neonatologist made decision to treat patent ductus arteriosus Exclusion Criteria: No parental consent Infants > 21days of postnatal age Congenital anomalies such as cardiac or multiple anomalies Infection (e.g., septicemia, pneumonia) Bleeding disorder or platelet count< 50,000/ml Acute kidney injury (AKI)defined as oliguria (urine output< 0.5 ml/kg/hr for 16hrs) and/or serum creatinine > 1.5 mg/dl Elevated liver enzymes (>2 fold from upper normal limits) Pulmonary hypertension or right to left shunt through the ductus arteriosus Diagnosis of necrotizing enterocolitis Unable to tolerate oral medications at the time of enrollment.

Ages Eligible for Study
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Minimum Age: 5 Days
Maximum Age: 21 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ibuprofen and acetaminophen arm (intervention arm)<br>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<br>* Intravenous ibuprofen given concomitantly with oral acetaminophen<br>|
| Active Comparator: ibuprofen and placebo arm (control arm)<br>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<br>* Intravenous ibuprofen given concomitantly with oral placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ductus Arteriosus Closure/Constriction Rate | 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 |  | 24-48 hours after the completion of study intervention | 
| Ventilatory Settings Before and After the Study Intervention |  | 24-48 hours after the completion of study intervention | 
| Rate of Liver Injury | liver enzymes before and after the study intervention | 24-48 hours after the completion of study intervention | 
| Rate of Renal Injury | Blood urea nitrogen (BUN) and serum creatinine before and after the study intervention | 24-48 hours after the completion of study intervention | 
| Rate of Hematological Adverse Events | Hematocrit and platelets before and after the study intervention | 24-48 hours after the completion of study intervention | 
| Total Number of Days of Mechanical Ventilation |  | from randomization until discharge/40 weeks post menstrual age | 
| Total Number of Days of Need for Supplemental Oxygen |  | from randomization until discharge/40 weeks post menstrual age | 
| Duration of Noninvasive Ventilation |  | from randomization until discharge/40 weeks post menstrual age | 
| Rate of Persistence of Ductus-needing Pharmacological Treatment |  | from randomization until discharge/40 weeks post menstrual age | 
| Rate of Surgical Ligation of PDA |  | from randomization until discharge/40 weeks post menstrual age | 
| Rate of Bronchopulmonary Dysplasia |  | at 36 weeks post menstrual age | 
| Percentage of Infants Requiring Home Oxygen Therapy |  | at discharge/40 weeks post menstrual age | 
| Death Before Discharge |  | until discharge/40 weeks post menstrual age | 
| Time to Achieve Full Enteral Feeding | Time to achieve 120 ml/kg/day of enteral feeding | from birth until discharge/40 weeks post menstrual age | 
| Days on Total Parenteral Nutrition |  | from birth until discharge/40 weeks post menstrual age | 
| Retinopathy of Prematurity |  | from birth until discharge/40 weeks post menstrual age | 
| Rate of Spontaneous Intestinal Perforation |  | from randomization until discharge/40 weeks post menstrual age | 
| Rate of Necrotizing Enterocolitis |  | from randomization until discharge/40 weeks post menstrual age | 
| Rate of Gastrointestinal Hemorrhage |  | from randomization until discharge/40 weeks post menstrual age | 
| Rate of Late Onset Sepsis |  | from randomization until discharge/40 weeks post menstrual age | 
| Length of Hospital Stay |  | from birth until discharge/40 weeks post menstrual age | 
| Rate of Periventricular Leukomalacia |  | from randomization until discharge/40 weeks post menstrual age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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patent ductus arteriosus, acetaminophen, ibuprofen, bronchopulmonary dysplasia, mechanical ventilation