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

Proportion of Participants With Ductus Arteriosus Closure/Constriction

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

Echocardiographic parameters including ductal size (PDA size in mm), Left atrium to aortic root ratio, ductal velocity, descending aortic diastolic flow, before and after the intervention. Between the group and within the group comparison

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

Ventilatory Settings Before and After the Study Intervention

Ventilator parameters including Fio2, Mean airway pressure, Peak Inspiratory pressure, PEEP, and ventilatory rate oxygenation indices including Oxygenation index and Respiratory Severity score before and after intervention

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

Proportion of Participants With Liver Injury

liver enzymes compared before and after the study intervention; if any significant elevation of liver enzymes from baseline, the participant classified as having liver injury

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

Proportion of Participants With Renal Injury

Blood urea nitrogen (BUN) and serum creatinine before and after the study intervention are compared. Participants exhibiting significant elevation BUN and S creatine, are classified as having renal injury

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

Proportion of Participants With Hematological Adverse Events

Hematocrit and platelet counts compared before and after the study intervention; if any significant alteration from baseline, the participant classified as having hematological adverse event,

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

Total Number of Days of Mechanical Ventilation

The total number of days on mechanical ventilation are counted as total duration of conventional mechanical ventilation plus high frequency ventilatory days

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

Total Number of Days of Need for Supplemental Oxygen

Cumulative days on any supplemental O2 (including Mechanical ventilation., noninvasive ventilation, nasal cannula support) calculated from randomization until 4 weeks of postmenstrual age

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

Duration of Noninvasive Ventilation

Total cumulative days on noninvasive ventilation, including NIPPV and nasal CPAP,

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

Proportion of Participants With Persistence of Ductus-needing Pharmacological Treatment

Proportion of participants in each group requiring open label treatment with pharmacological agents for ductal closure, e.g. IV Ibuprofen or IV Acetaminophen or IV indomethacin therapies, as decided by the treating physician

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

Proportion of Participants Requiring Surgical Ligation of PDA

Proportion of participants in each group requiring surgical ligation of persistent PDA for definitive surgical closure

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

Proportion of Participants Developing Bronchopulmonary Dysplasia

Proportion of participants diagnosed to have BPD based supplemental O2 requirement at 36 weeks' postmenstrual age

Time frame: at 36 weeks post menstrual age

Percentage of Infants Requiring Home Oxygen Therapy

Proportion of participants in each group requiring home-based supplemental O2 therapy following the initial discharge from hospital.

Time frame: at discharge/40 weeks post menstrual age

Proportion of Participants Developing Death Before Discharge

Proportion of participants in each group developing in-hospital death prior to 40 weeks of postmenstrual age.

Time frame: until discharge/40 weeks post menstrual age

Time to Achieve Full Enteral Feeding

Duration days during the postnatal period required to achieve an enteral feeding volume of 120 ml/kg/day.

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

Total Days on Total Parenteral Nutrition

Cumulative days of receiving total parental nutrition from birth until the participant is discharged or reached postmenstrual age of 40 weeks

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

Proportion of Participants With Retinopathy of Prematurity

Proportion of participants in each group diagnosed to have retinopathy of prematurity

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

Proportion of Participants Developing Spontaneous Intestinal Perforation

Proportion of participants developing or having the diagnosis of spontaneous intestinal perforation from randomization until discharge or 40 weeks' Postmenstrual age

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

Proportion of Participants Developing Necrotizing Enterocolitis

Proportion of participants in each group with the diagnosis of medical or surgical Necrotizing Enterocolitis

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

Proportion of Participants Developing Gastrointestinal Hemorrhage

Proportion of participants in each group developing gastrointestinal hemorrhage following randomization until discharge or postmenstrual age of 40 weeks

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

Proportion of Participants Developing Late Onset Sepsis

Proportion of participants diagnosed to have either probable sepsis with minimum of 7 days of antibiotic therapy or culture proven sepsis

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

Length of Hospital Stay

Total duration (in days ) of hospital stay

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

Proportion of Participants With Periventricular Leukomalacia

Proportion of participants in each group with the evidence of periventricular leukomalacia on neurosonography

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