Clinical trial NCT03701074: 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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Patent Ductus Arteriosus
Preterm Infant
Bronchopulmonary Dysplasia
Keywords: patent ductus arteriosus
acetaminophen
ibuprofen
bronchopulmonary dysplasia
mechanical ventilation
Lead sponsor: University of South Alabama
Sponsor class: OTHER
First posted: 2018-10-09
Enrollment: 1
Sex: ALL
Minimum age (years): 5
Maximum age (years): 21
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Ductus Arteriosus Closure/Constriction Rate
timeFrame: 24-48 hours after the completion of study intervention
Secondary outcomes:
measure: Echocardiographic Patent Ductus Arteriosus Parameters Before and After the Study Intervention
timeFrame: 24-48 hours after the completion of study intervention
measure: Ventilatory Settings Before and After the Study Intervention
timeFrame: 24-48 hours after the completion of study intervention
measure: Rate of Liver Injury
timeFrame: 24-48 hours after the completion of study intervention
measure: Rate of Renal Injury
timeFrame: 24-48 hours after the completion of study intervention
measure: Rate of Hematological Adverse Events
timeFrame: 24-48 hours after the completion of study intervention
measure: Total Number of Days of Mechanical Ventilation
timeFrame: from randomization until discharge/40 weeks post menstrual age
measure: Total Number of Days of Need for Supplemental Oxygen
timeFrame: from randomization until discharge/40 weeks post menstrual age
measure: Duration of Noninvasive Ventilation
timeFrame: from randomization until discharge/40 weeks post menstrual age
measure: Rate of Persistence of Ductus-needing Pharmacological Treatment
timeFrame: from randomization until discharge/40 weeks post menstrual age
measure: Rate of Surgical Ligation of PDA
timeFrame: from randomization until discharge/40 weeks post menstrual age
measure: Rate of Bronchopulmonary Dysplasia
timeFrame: at 36 weeks post menstrual age
measure: Percentage of Infants Requiring Home Oxygen Therapy
timeFrame: at discharge/40 weeks post menstrual age
measure: Death Before Discharge
timeFrame: until discharge/40 weeks post menstrual age
measure: Time to Achieve Full Enteral Feeding
timeFrame: from birth until discharge/40 weeks post menstrual age
measure: Days on Total Parenteral Nutrition
timeFrame: from birth until discharge/40 weeks post menstrual age
measure: Retinopathy of Prematurity
timeFrame: from birth until discharge/40 weeks post menstrual age
measure: Rate of Spontaneous Intestinal Perforation
timeFrame: from randomization until discharge/40 weeks post menstrual age
measure: Rate of Necrotizing Enterocolitis
timeFrame: from randomization until discharge/40 weeks post menstrual age
measure: Rate of Gastrointestinal Hemorrhage
timeFrame: from randomization until discharge/40 weeks post menstrual age
measure: Rate of Late Onset Sepsis
timeFrame: from randomization until discharge/40 weeks post menstrual age
measure: Length of Hospital Stay
timeFrame: from birth until discharge/40 weeks post menstrual age
measure: Rate of Periventricular Leukomalacia
timeFrame: from randomization until discharge/40 weeks post menstrual age
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama
state: Alabama
Study officials:
affiliation: University of South Alabama
name: Fabien Eyal, MD
role: STUDY_DIRECTOR
References: