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

Phase 2

Terminated

• Conditions: Patent Ductus Arteriosus; Preterm Infant; Bronchopulmonary Dysplasia
• Interventions: Drug: Ibuprofen and acetaminophen; Drug: Ibuprofen and placebo

• Registration Number: NCT03701074
• Lead Sponsor: University of South Alabama

Brief Summary

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

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 Timeline

• Study First Submitted: 2018-08-22
• Study First Submitted QC: 2018-10-05
• Study First Posted: 2018-10-09
• Study Start: 2018-12-15
• Primary Completion: 2020-10-30
• Study Completion: 2020-12-02
• Status Verified: 2021-04
• Results First Submitted: 2021-04-18
• Results First Submitted QC: 2021-04-18
• Last Update Submitted: 2021-04-18
• Results First Posted: 2021-05-11
• Last Update Posted: 2021-05-11

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 1

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ibuprofen and acetaminophen arm (intervention arm)	Ibuprofen and acetaminophen	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).
ibuprofen and placebo arm (control arm)	Ibuprofen and placebo	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.

Primary Outcome Measures

Name	Time	Method
Ductus Arteriosus Closure/Constriction Rate	24-48 hours after the completion of study intervention	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

Secondary Outcome Measures

Name	Time	Method
Ventilatory Settings Before and After the Study Intervention	24-48 hours after the completion of study intervention
Echocardiographic Patent Ductus Arteriosus Parameters Before and After the Study Intervention	24-48 hours after the completion of study intervention
Rate of Liver Injury	24-48 hours after the completion of study intervention	liver enzymes before and after the study intervention
Rate of Renal Injury	24-48 hours after the completion of study intervention	Blood urea nitrogen (BUN) and serum creatinine before and after the study intervention
Rate of Periventricular Leukomalacia	from randomization until discharge/40 weeks post menstrual age
Rate of Hematological Adverse Events	24-48 hours after the completion of study intervention	Hematocrit and platelets before and after the 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
Rate of Persistence of Ductus-needing Pharmacological Treatment	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	from birth until discharge/40 weeks post menstrual age	Time to achieve 120 ml/kg/day of enteral feeding
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 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
Duration of Noninvasive Ventilation	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 Necrotizing Enterocolitis	from randomization until discharge/40 weeks post menstrual age
Length of Hospital Stay	from birth until discharge/40 weeks post menstrual age

Trial Locations

Locations (1)

University of South Alabama; 🇺🇸 Mobile, Alabama, United States