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

University of South Alabama (USA)

Status and phase: Terminated; Phase 2

Conditions: Preterm Infant; Bronchopulmonary Dysplasia; Patent Ductus Arteriosus

Treatments: Drug: Ibuprofen and acetaminophen; Drug: Ibuprofen and placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT03701074

15-081/730216-8

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1 patient

Sex: All

Ages: 5 to 21 days old

Volunteers: No 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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1 participants in 2 patient groups

ibuprofen and acetaminophen arm (intervention arm)

Experimental group

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).

Treatment:

Drug: Ibuprofen and acetaminophen

ibuprofen and placebo arm (control arm)

Active Comparator group

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.

Treatment:

Drug: Ibuprofen and placebo