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

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.

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.