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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

Primary Purpose

Patent Ductus Arteriosus, Preterm Infant, Bronchopulmonary Dysplasia

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ibuprofen and acetaminophen
Ibuprofen and placebo
Sponsored by
University of South Alabama
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Patent Ductus Arteriosus focused on measuring patent ductus arteriosus, acetaminophen, ibuprofen, bronchopulmonary dysplasia, mechanical ventilation

Eligibility Criteria

5 Days - 21 Days (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of South Alabama

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

ibuprofen and acetaminophen arm (intervention arm)

ibuprofen and placebo arm (control arm)

Arm Description

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 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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Echocardiographic Patent Ductus Arteriosus Parameters Before and After the Study Intervention
Ventilatory Settings Before and After the Study Intervention
Rate of Liver Injury
liver enzymes before and after the study intervention
Rate of Renal Injury
Blood urea nitrogen (BUN) and serum creatinine before and after the study intervention
Rate of Hematological Adverse Events
Hematocrit and platelets before and after the study intervention
Total Number of Days of Mechanical Ventilation
Total Number of Days of Need for Supplemental Oxygen
Duration of Noninvasive Ventilation
Rate of Persistence of Ductus-needing Pharmacological Treatment
Rate of Surgical Ligation of PDA
Rate of Bronchopulmonary Dysplasia
Percentage of Infants Requiring Home Oxygen Therapy
Death Before Discharge
Time to Achieve Full Enteral Feeding
Time to achieve 120 ml/kg/day of enteral feeding
Days on Total Parenteral Nutrition
Retinopathy of Prematurity
Rate of Spontaneous Intestinal Perforation
Rate of Necrotizing Enterocolitis
Rate of Gastrointestinal Hemorrhage
Rate of Late Onset Sepsis
Length of Hospital Stay
Rate of Periventricular Leukomalacia

Full Information

First Posted
August 22, 2018
Last Updated
April 18, 2021
Sponsor
University of South Alabama
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1. Study Identification

Unique Protocol Identification Number
NCT03701074
Brief Title
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
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Terminated
Why Stopped
very slow enrollment. Only one patient enrolled. Termination by PI
Study Start Date
December 15, 2018 (Actual)
Primary Completion Date
October 30, 2020 (Actual)
Study Completion Date
December 2, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of South Alabama

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Patent Ductus Arteriosus, Preterm Infant, Bronchopulmonary Dysplasia
Keywords
patent ductus arteriosus, acetaminophen, ibuprofen, bronchopulmonary dysplasia, mechanical ventilation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Days
Maximum Age & Unit of Time
21 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fabien Eyal, MD
Organizational Affiliation
University of South Alabama
Official's Role
Study Director
Facility Information:
Facility Name
University of South Alabama
City
Mobile
State/Province
Alabama
ZIP/Postal Code
36607
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

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

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