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 2TerminatedNCT03701074

University of South Alabama1 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Patent Ductus Arteriosus

Eligibility

Sex: ALLMin age: 5 DaysMax age: 21 Days

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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

Time frame: 24-48 hours after the completion of study intervention

Secondary Outcomes

Echocardiographic Patent Ductus Arteriosus Parameters Before and After the Study Intervention

Time frame: 24-48 hours after the completion of study intervention

Ventilatory Settings Before and After the Study Intervention

Time frame: 24-48 hours after the completion of study intervention

Rate of Liver Injury

liver enzymes before and after the study intervention

Time frame: 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

Time frame: 24-48 hours after the completion of study intervention

Rate of Hematological Adverse Events

Hematocrit and platelets before and after the study intervention

Time frame: 24-48 hours after the completion of study intervention

Total Number of Days of Mechanical Ventilation

Time frame: from randomization until discharge/40 weeks post menstrual age

Total Number of Days of Need for Supplemental Oxygen

Time frame: from randomization until discharge/40 weeks post menstrual age

Duration of Noninvasive Ventilation

Time frame: from randomization until discharge/40 weeks post menstrual age

Rate of Persistence of Ductus-needing Pharmacological Treatment

Time frame: from randomization until discharge/40 weeks post menstrual age

Rate of Surgical Ligation of PDA

Time frame: from randomization until discharge/40 weeks post menstrual age

Rate of Bronchopulmonary Dysplasia

Time frame: at 36 weeks post menstrual age

Percentage of Infants Requiring Home Oxygen Therapy

Time frame: at discharge/40 weeks post menstrual age

Death Before Discharge

Time frame: until discharge/40 weeks post menstrual age

Time to Achieve Full Enteral Feeding

Time to achieve 120 ml/kg/day of enteral feeding

Time frame: from birth until discharge/40 weeks post menstrual age

Days on Total Parenteral Nutrition

Time frame: from birth until discharge/40 weeks post menstrual age

Retinopathy of Prematurity

Time frame: from birth until discharge/40 weeks post menstrual age

Rate of Spontaneous Intestinal Perforation

Time frame: from randomization until discharge/40 weeks post menstrual age

Rate of Necrotizing Enterocolitis

Time frame: from randomization until discharge/40 weeks post menstrual age

Rate of Gastrointestinal Hemorrhage

Time frame: from randomization until discharge/40 weeks post menstrual age

Rate of Late Onset Sepsis

Time frame: from randomization until discharge/40 weeks post menstrual age

Length of Hospital Stay

Time frame: from birth until discharge/40 weeks post menstrual age

Rate of Periventricular Leukomalacia

Time frame: from randomization until discharge/40 weeks post menstrual age

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes