Clinical trial NCT03701074
Conditions: Patent Ductus Arteriosus Preterm Infant Bronchopulmonary Dysplasia
Keywords: patent ductus arteriosus acetaminophen ibuprofen bronchopulmonary dysplasia mechanical ventilation
Sponsor: University of South Alabama
Start date: 2018-12-15; Completion date: 2020-12-02
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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). arm 2: 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.
Interventions: intervention 1: Ibuprofen and acetaminophen intervention 2: Ibuprofen and placebo
Intervention descriptions: intervention 1: Intravenous ibuprofen given concomitantly with oral acetaminophen intervention 2: Intravenous ibuprofen given concomitantly with oral placebo

Protocol documents:
Prot_SAP_000.pdf: 
July 2018, rev 3 
 
Page 1 of 17 
Protocol 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. 
 
Drug substance  
Investigated:   
Oral acetaminophen 
 
Principal Investigator: Ramachandra Bhat, M.D. 
 
Study monitors:  
Ellen Dean, R.N. 
Gina Massey, R.N. 
Ariel Salas, M.D. 
 
Co-investigators:  
Emily Kelley, PharmD  
Robert Smith, RPh  
Lynn Batten, M.D. 
Gary Carnahan, M.D. 
Fabien Eyal, M.D. 
Richard Whitehurst,M.D.  
Michael Zayek, M.D. 
 
Background 
 
Ductus arteriosus is a vital arterial connection between the pulmonary and systemic fetal circulation. It 
allows blood enriched in oxygen and nutrient, returning from the placenta, to bypass the lungs and to 
readily reach the lower parts of the body of the fetus. This flow of blood from the pulmonary 
circulation to systemic circulation is driven by the higher pulmonary vascular resistance and pressure 
as compared to the systemic ones. After birth, as pulmonary circulation dilates and pulmonary  vascular 
pressure and resistance decrease,  all right ventricular cardiac output shifts to the lung and subsequently 
the ductus arteriosus closes. 
 
In preterm infants, the ductus arteriosus may remain open after birth, known as persistent PDA 
(pPDA). Approximately 50% of preterm infants with birth weight <1000 g develop pPDA. As the 
incidence of a pPDA is inversely proportional to birth weight (BW) and gestational age, a 
hemodynamically active PDA (defined as carrying a significant blood flow from the aorta to the lung) 
is a very common morbidity in extremely low birth weight infants (ELBWI, BW <1000 grams). After 
birth, the blood flowing through a PDA contributes to a higher pulmonary blood flow, (significant left 
to right shunt, Aorto-pulmonary  shunt) leading to left ventricular  overload. As a result, 
hemodynamically significant pPDAs are associated with prolonged mechanical ventilation, and higher 
occurrences of hypotension, pulmonary hemorrhage, bronchopulmonary dysplasia, necrotizing 
enterocolitis, retinopathy, intraventricular hemorrhage, and abnormal cerebral and intestinal perfusion 
in the ELBWI1, 2, 3, 4. 
 
The mechanism of pPDA in ELBWI is not well known. Failure of the ductus arteriosus to constrict 
may be partly mediated by the immaturity of the signaling pathways for vasodilators and 
vasoconstrictors.  After birth, all newborn infants are exposed to a sudden oxidative stress and 
experience a surge in the reactive oxygen species (ROS). These ROS contribute to the closure of the 
PDA after birth. Prostaglandin F2 a (PGF2a) is an established marker for oxidative stress and also 
produces smooth muscle cell contraction (used to induce labor).  Elevated levels of PGF2a are usually 
found in all newborn infants during the first weeks of age. Chen, et al., have found that PGF2a 
produces ductal closure in mature mice born at term gestational age while it induces dilation of the 


July 2018, rev 3 
 
Page 2 of 17 
•
•.
ductus in preterm mice5.  1n addition, the ductus arteriosus in preterm infants has an increased 
sensitivity to vasodilators, such as prostaglandin E2 and to nitric oxide (6,7). 
 
NSAIDs (non-steroidal anti-inflammatory drugs) inhibit the production of prostaglandins by their non-
selective inhibition of the cyclooxygenase-1and cyclooxygenase-2 (COX-1and COX-2)8.  They are the 
first line of therapy for hemodynamically active PDAs (significant aorta-pulmonary shunt). However, the 
undesirable complications associated with NSAIDs, such as necrotizing enterocolitis and isolated small 
bowel perforation, limit their daily dosage and their duration of therapy. In addition, their ability to 
close a patent ductus arteriosus decreases with lower gestational age. Higher mortality and morbidity 
rates are associated with failure to close a PDA9, 10.  Failure to respond to treatment will require 
successive courses of ibuprofen or may resort to surgical intervention. Published reports have 
demonstrated high rates of long term neurological complications associated with surgical closure of a 
ductus arteriosus 11,12.   
 
Recently, two randomized controlled studies found that the effectiveness of oral acetaminophen was 
equivalent to the use of oral ibuprofen as a first line treatment of PDAs in preterm infants13 14.   Recently 
performed RCT, comparing intravenous administration of ibuprofen, indomethacin and acetaminophen, 
has found that intravenous administration of acetaminophen has similar efficacy in constricting the ductus 
when compared to the standard treatment regimens involving indomethacin and ibuprofen. This study 
also found very high rate of ductal constriction, 80%, in preterm infants who received IV acetaminophen, 
higher than the previously reported rates.17 In addition, acetaminophen appears to have selective 
inhibitory actions on COX-2 15.  Furthermore, COX-2 inhibitors were able to constrict the ductus 
arteriosus in fetal lambs 16.   
 
While acetaminophen seems a promising alternative to Ibuprofen, it could add its beneficial 
constrictive effects on the ductus arteriosus without potentiating similar undesirable effects seen 
with NSAIDs. Inability to close the ductus arteriosus with ibuprofen is common (more than 
30%), leading to prolonged duration of ventilation, unstable cardiovascular system, and higher 
occurrence of long term morbidities. The combination of acetaminophen and ibuprofen therapy 
could be beneficial and may improve the ductal constriction rate when compared to the regimen 
wherein they are used alone. This combined therapy is under investigation currently. Out Of 
two studies conducted, one study has been published recently.18 Other study is still recruiting 
the infants. The published study demonstrated a trend towards higher rates of PDA closure 
among infants treated with combination of ibuprofen and acetaminophen as opposed to 
ibuprofen alone. No increased risk for adverse events reported in that study.  
 
Hypothesis 
 
The hypothesis is to determine whether treatment of hemodynamically significant PDA with a 
combined therapy of intravenous Ibuprofen and oral acetaminophen has higher success rate in 
closing the ductus arteriosus than standard ibuprofen alone therapy in preterm infants. 
 
1) Primary outcome: 
 
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. 
 
2) Secondary outcome: 
 
Echocardiographic ductal parameters before and after intervention: ductal size, Left atrium to aortic root 
ratio, ductal velocity, descending aortic diastolic flow 


July 2018, rev 3 
 
Page 3 of 17 
Ventilator parameters and oxygenation index before and after intervention 
Ventilation days 
Duration of Oxygen treatment 
Duration of CPAP 
Total no. PDA treatments after the study interventions 
Need for PDA ligation 
BPD at 36 weeks 
Home Oxygen need 
Retinopathy of prematurity 
Feeding intolerances 
Gastrointestinal perforation 
Necrotizing enterocolitis 
Gastrointestinal hemorrhage 
Duration of hospital stay 
Duration of TPN 
Late onset sepsis 
Need for late corticosteroid treatment post study intervention 
 
3) Safety outcomes 
Death 
Elevated liver enzymes 
Acute kidney injury 
Feeding intolerance while on study intervention 
GI hemorrhage 
Intestinal perforation after the initiation of study intervention 
NEC after the initiation of study intervention 
Thrombocytopenia 
 
Data collection; 
All the pertinent baseline maternal and neonatal clinical-sociodemopgraphic data will be collected 
prospectively by accessing the maternal and neonatal electronic medical records. All the pertinent 
postnatal clinical, biochemical and echocardiographic data will be collected prospectively all the newborn 
infants enrolled in the study so as to define all the primary, secondary and safety outcome variables. Even 
if infant is withdrawn from the study, data collection will be continued as it is an intention-to-treat 
analysis. 
 
References 
 
1. Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics 
2010;125:1020-30. 
 
2. Ohlsson A, Walia R, Shah 55. Ibuprofen for the treatment of patent ductus arteriosus in preterm 
and/or low birth weight infants. Cochrane Database Syst Rev 2010;4:CD003481. 
 
3. Clyman Rl. Mechanisms regulating the ductus arteriosus. Bioi Neonate. 2006;89(4):330-5. 
 
4. Heuchan AM, Clyman Rl. Managing the patent ductus arteriosus: current treatment options. Arch 
Dis Child Fetal Neonatal Ed. 2014 Sep;99(5):F431-6. doi: 10.1136/archdischild-2014-306176. 
 
5. Chen JX, O'Mara PW, Poole SD, Brown N, Ehinger NJ, Slaughter JC, Paria BC, Aschner JL, 
Reese J. lsoprostanes as physiological mediators of transition to newborn life: novel mechanisms 


July 2018, rev 3 
 
Page 4 of 17 
regulatingpatency of the term and preterm ductus arteriosus.Pediatr Res. 2012 Aug;72(2):122-8. 
 
6. Clyman Rl, Waleh N, Black SM,Riemer RK, Mauray F,Chen YQ: Regulation of ductus arteriosus 
patency by nitric oxide in fetal lambs. The role of gestation, oxygen tension and vasavasorum. 
Pediatr Res 1998; 43: 633-644. 
 
 
7. Seidner SR, Chen YQ, Oprysko PR, Mauray  F, Tse MM, LinE, Koch C, Clyman Rl: combined 
prostaglandin and nitric oxide inhibition produces anatomic remodeling and closure of the ductus 
arteriosus in the premature  newborn baboon. Pediatr Res 2001; 50: 365-373. 
 
8. Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like 
drugs. Nat New Bioi 231:232-235 
 
9. Cassady G,Crouse DT, Kirklin JW, et al. A randomized,controlled trial of very early prophylactic 
ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. N Engl J Med 
1989;320:1511-696. 
 
10. Brooks JM, Travadi JN, Patole SK, et al. Is surgical ligation of patent ductus arteriosus  
necessary?  The Western Australian experience of conservative management. Arch Dis Child 
Fetal Neonatal, Ed. 2005;90:F235-9. 
 
11. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, et al (2007) Neurosensory impairment 
after surgical closure of patent ductus arteriosus in extremely  low birth weight infants: results 
from the Trial of Indomethacin Prophylaxis in Preterms J Pediatr (150): 229-234,234.el. 
 
12. Malviya M, Ohlsson A, Shah 5 (2008) Surgical versus medical treatment with cyclooxygenase 
inhibitors for symptomatic patent ductus arteriosus in preterm  infants. Cochrane 
DatabaseSystRev (1): CD003951 
 
13. Oncel MY, Yurttutan 5, Erdeve 0, Uras N2, Altug N, Oguz 55, Canpolat FE,Dilmen U.Oral 
paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm 
infants: a randomized controlled trial. J Pediatr. 2014 Mar;164(3):510-4. 
 
14. Dang D, Wang D, Zhang C,Zhou W,Zhou Q, Wu H. Comparison of oral paracetamol versus 
ibuprofen in premature  infants with patent  ductus arteriosus: a randomized controlled trial. PloS 
One. 2013 Nov 4;8(11):e77888 
 
15. Boutaud 0, Aronoff DM, Richardson JH, Marnett U, Oates JA (2002) Determinants of the cellular 
specificity of acetaminophen as an inhibitor of prostaglandin  H2 synthases. Proc NatiAcadSci 
USA 99:7130-7135 
 
16. Takahashi Y, Roman C, Chemtob 5, Tse MM, LinE,Heymann  MA, Clyman Rl. 
Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo. 
Am J PhysioiRegullntegr Camp Physiol. 2000 Jun;278{6):R1496-505. 
 
17. El-Mashad AE, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and 
safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in 
preterm neonates. Eur J Pediatr. 2017 Feb;176(2):233-240. 
 
18. Hochwald O, Mainzer G, Borenstein-Levin L, Jubran H, Dinur G, Zucker M, Mor M, Khoury A, 


July 2018, rev 3 
 
Page 5 of 17 
Kugelman A. Adding Paracetamol to Ibuprofen for the Treatment of Patent Ductus Arteriosus in 
Preterm Infants: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. Am J Perinatol. 
2018 May 21. doi: 10.1055/s-0038-1653946. [Epub ahead of print] 
 
 
 


July 2018, rev 3 
 
Page 6 of 17 
Methods 
 
Study type:  
This study is a single center, randomized, double blinded, placebo controlled trial 
 
Population:  Preterm infants with gestational age of with a gestational age ≤27 6/7 weeks by the best 
obstetric estimate. 
 
Sample size estimation:    A chart review was conducted to assess the success rate of PDA closure 
after the first course of ibuprofen among ELBWI. It was determined that 60% of ELBWI treated for a 
persistent PDA with ibuprofen did not need a second course or surgical intervention.  Aa total sample 
size of 72 ELBWI would be required to detect at least a 30% absolute increase (from 60% to 90%) in 
the success rate of PDA closure using combined  ibuprofen-acetaminophen therapy with  a type II error 
of .20 (power of 80%) and a type I error of .05 (two-tailed). Due to a possibility of withdrawal of 
infants from the study, due to feeding intolerance, poor tolerance to oral acetaminophen or made 
NPO for other reasons, sample size will inflated by 10% Hence, total no. infants required will be 
80. Analysis will be based on intention-to treat. 
 
Inclusion criteria: 
 
Infants will be included in the study if ALL three following criteria are met: 
 
1. Written parental consent is obtained 
2. Infant requires respiratory  support (assisted ventilation or CPAP) 
3. diagnosis of a persistent h e mo d y n a m i c a l l y  s i g n i f i c a n t  PDA after 5 days of age, 
defined a s  d u ct a l  si ze  ≥ 1.5 mm a n d  a t  l e a s t o n e  o f  t h e  f o ll o wi ngs :   
 
a)  Maximum flow velocity through the ductus ≤ 2 m/s  
b) Left atrium to aorta ratio ≥ 1.4 
c)  Wide pulse pressure  
d)   Elevated BNP > 200 
e) systemic hypoperfusion: metabolic acidosis with base deficit ≥ 10 mEq/L 
       4. Attending neonatologist made decision to treat PDA 
 
Exclusion criteria: 
 
1. No parental consent 
2. Infants < 5 days and > 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 normal levels) 
8. Pulmonary hypertension or right to left shunt through the ductus arteriosus 
9. Diagnosis of necrotizing enterocolitis 
10. Unable to tolerate oral medications or NPO at the time of enrollment. (if NPO after 
enrollment, withdrawn from the study)  
11. Infants on postnatal corticosteroid treatment for treating parenchymal lung disease 
Study Objectives and overview: 
 
The primary objectives of the study are to confirm the safety of oral acetaminophen in extremely low 


July 2018, rev 3 
 
Page 7 of 17 
birth infants, given concomitantly with ibuprofen and also to determine its efficacy in significantly 
increasing the rates of ductal closure when compared to only ibuprofen therapy. Hence primary 
outcome variable include PDA closure success rate, based on the 2-D transthoracic echocardiographic  
evidence, with in the time frame of seven days following the study interventions.  Secondary 
objectives are to exclude the need for further medical management to close PDA which includes 
subsequent intravenous ibuprofen courses (standard of care) or surgical intervention to close the 
ductus arteriosus (surgical PDA ligation), duration  of mechanical ventilation, requirement of steroid 
therapy, incidence of necrotizing enterocolitis, small bowel perforation, bronchopulmonary 
dysplasia, nosocomial sepsis, retinopathy of prematurity, and death. 
 
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 1:1parallel allocation. Allocation group (either treatment group or placebo group) will be 
labelled on a card and the card will be sealed in an opaque envelope. The sealed envelope will be 
labelled serially and opened sequentially after enrolling infants in to the study. The pharmacist will 
pick the envelope corresponding to the subgroup of the patient, based on subject's gestational age. 
 
Several small, sealed, non-transparent, and serially numbered envelopes will be placed into one large 
envelope. The pharmacist will open a small envelope with the lowest serial number (next available 
number). In each of these small envelopes is an assigned treatment with a second card detailing the 
labs required for the study.  The pharmacist will distribute the second a card to the lab personnel, 
detailing the labs needed on the blood sample collected.  
 
Protocol 
 
An infant is randomized into the study if all inclusion criteria are met.  
 
 Before the beginning of the intervention: 
A.  
1. Confirm the presence of parental consent in the chart 
2. Check if infant is on caffeine citrate. If he/she is not, start the infant on caffeine citrate per 
standard caffeine orders and standard unit's policy. 
3. CBC with diff (if baseline CBC not available), BUN, creatinine, BNP (if baseline BNP not 
available), AST and ALT 
4. Collect urine for specific gravity 
5. Confirm that infant has appropriate urine output (> 4 wet diapers per day)  
 
B. Randomization: 
 
1. Order written to treat PDA per study protocol 
 
2. Infant will be randomized by a pharmacist to one of the two treatment arms. 
 
a) Ibuprofen-acetaminophen arm (intervention arm): lbuprofen and acetaminophen will 
be administered concomitantly. 
 
Intravenous  Ibuprofen is the mode of administration. The dose of ibuprofen will be the 
standard dose used in our NICU, which include dosing based on the postnatal age. Infants 
< 70 h of age: 10 mg/kg/dose loading dose followed by 5 mg/kg/daose, two doses at q24 


July 2018, rev 3 
 
Page 8 of 17 
intervals, started 24 h after the loading dose. Infants aged 70 -108 h: 14 mg/kg/dose 
loading dose followed by 7 mg/kg/dose, two doses at q24 intervals, started 24 h after the 
loading dose. Infants > 108 h: 18 mg/kg/dose loading dose followed by 9 mg/kg/dose, 
two doses at q24 intervals, started 24 h after the loading dose. This ibuprofen dosing 
regimen is as per the standard of care at our NICU.  Acetaminophen will be administered 
as oral formulation d. Acetaminophen is given at a dose of 15 mg/Kg q 6 hours for 3 days 
(complete total of 12 doses). Intervention will be only for 3 days. After three days of 
intervention, if PDA still open, decision to close and medication choice will be as per the 
attendings’ discretion and as per our standard of care.  
 
 
b) Ibuprofen-placebo arm (control arm): Intravenous Ibuprofen is the mode of 
administration. The dose of ibuprofen will be the standard dose used in our NICU, which 
include dosing based on the postnatal age. Infants < 70 h of age: 10 mg/kg/dose loading 
dose followed by 5 mg/kg/dose, two doses at q24 intervals, started 24 h after the loading 
dose. Infants aged 70 -108 h: 14 mg/kg/dose loading dose followed by 7 mg/kg/daose, 
two doses at q24 intervals, started 24 h after the loading dose. Infants > 108 h: 18 
mg/kg/dose loading dose followed by 9 mg/kg/dose, two doses at q24 intervals, started 
24 h after the loading dose. This ibuprofen dosing regimen is as per the standard of care 
at our NICU 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. Intervention will be only for 3 days. After three days of intervention, if PDA 
still open, decision to close and medication choice will be as per the attendings’ 
discretion and as per our standard of care.  
 
Day1-3 of intervention: 
 
1. Urine output and urine specific gravity monitored daily 
2. Blood specimen collected and sent to lab for acetaminophen serum levels before the 8th dose. 
3. Obtain s. creatinine if oliguria (urine output< 0.5 ml/kg/hr for 16 hrs) develops  
 
Day 4 (+ 2 days)  of intervention (after the completion of 3 days of treatment) 
 
1. Obtain echocardiogram to assess the presence of a PDA. Preferably on day 4. If facility is not 
available, obtain within next 2 days.  
2. CBC with diff count, BNP and BUN, serum creatinine, ALT and AST and BNP   
3. The study interventions end after the 3 days of treatment. If PDA remains patent, it will be 
at the discretion of the attending to consider treatment or not. Medication use will be at the 
discretion of the attending. PDA will be managed as per our standard of practice. However, 
all the pertinent data will be collected prospectively for the analysis. 
 
Withdrawal of subject from the study 
 
The study intervention will be stopped immediately and subject will be withdrawn from the study if 
any of the following occur: 
 
1. Acetaminophen trough levels >30 microgram/ml (mg/L). This critical value will be called to the 
clinical team. 
2. Elevation of liver enzymes AST or ALT > 3 fold baseline values 
3. Stage 2 or greater neonatal AKI  is determined by oliguria (urine output< 0.5 ml/kg/hr for 12 hrs) 
and/or S. cr increases by 200% from baseline(≥ 2 fold increase). This definition is as per Kidney 


July 2018, rev 3 
 
Page 9 of 17 
Diseases Improving  global Outcomes (KDIGO) neonatal AKI definition.   
4. Gastrointestinal bleeding  
5. Necrotizing enterocolitis 
6. Unable to tolerate oral acetaminophen or made NPO for feeding intolerance 
Ordering laboratory tests for monitoring 
Blood samples will be obtained from all enrolled infants baseline, before the eighth dose of 
acetaminophen or placebo and after the completion of the study intervention . The blood sample will be 
labelled as "Study labs". Lab supervisors will have access to the randomization list and will identify 
infants randomized to acetaminophen and Ibuprofen arm to run the acetaminophen lab levels. All the 
infants enrolled in the study will be tested for BNP, LFTs and serum creatinine as standard of care. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCIU PROTOCOL 
Preterm ≤ 27 weeks 
Respiratory support 
PDA is present and treatment indicated 
Written Parental consent obtained 
Order written to "Start PDA study treatment 
protocol 
CBC with diff (if baseline CBC not available), BUN, creatinine, BNP (if 
baseline BNP not available), AST and  ALT 
 
Blood Specimen obtained for study drug serum 
levels, ± 1 hour before 8th dose of acetaminophen / 
placebo 
 
Day 4 (+ 2 days) Echocardiogram obtained. CBC 
with diff count, BNP and BUN, serum creatinine, 
ALT and AST and BNP    
Stop Study intervention:   
 
Study intervention will be for 3 days 
Acetaminophen 12 doses and 
ibuprofen 3 doses in Ibuprofen-
acetaminophen arm. Placebo 12 doses 
and ibuprofen 3 doses in ibuprofen –
placebo arm. 
Withdraw subject from study:   
 
Acetaminophen levels >30 microgram / ml)(mg/L) 
 
AKI (as defined above) 
 
GI hemorrhage or NEC 
 
Unable to tolerate oral acetaminophen or NPO* 
 
Elevation of liver enzymes AST or ALT > 3 fold 
baseline values 


July 2018, rev 3 
 
Page 10 of 17 
 
 
*NPO during study:  If infant is placed NPO while on study drug, enteral meds (acetaminophen or placebo) will be held. Infant will be withdrawn 
from the study.  
PDA Treatment Protocol to Pharmacy 
 
Pharmacist will open the next available envelope that assign the infant to one of the two groups 
Infants randomized to the Ibuprofen-acetaminophen arm will receive 
 
 
Ibuprofen dosing as per the standard of care at our NICU: The dose of ibuprofen will be the 
standard dose used in our NICU, which include dosing based on the postnatal age. Infants < 70 h 
of age: 10 mg/kg/dose loading dose followed by 5 mg/kg/dose, two doses at q24 intervals, started 
24 h after the loading dose. Infants aged 70 -108 h: 14 mg/kg/dose loading dose followed by 7 
mg/kg/dose, two doses at q24 intervals, started 24 h after the loading dose. Infants > 108 h: 18 
mg/kg/dose loading dose followed by 9 mg/kg/dose, two doses at q24 intervals, started 24 h after 
the loading dose. This ibuprofen dosing regimen is as per the standard of care at our NICU  
 
PO Acetaminophen at 15 mg/kg q 6 hours x12 doses 
 
Discontinue acetaminophen after dose #12. 
 
If infant is NPO; the subject will be withdrawn from the study. 
 
Infants randomized to the Ibuprofen-placebo arm will receive 
 
 
Ibuprofen dosing as per the standard of care at our NICU: The dose of ibuprofen will be the 
standard dose used in our NICU, which include dosing based on the postnatal age. Infants < 70 h 
of age: 10 mg/kg/dose loading dose followed by 5 mg/k/dose, two doses at q24 intervals, started 
24 h after the loading dose. Infants aged 70 -108 h: 14 mg/kg/dose loading dose followed by 7 
mg/kg/dose, two doses at q24 intervals, started 24 h after the loading dose. Infants > 108 h: 18 
mg/kg/dose loading dose followed by 9 mg/kg/dose, two doses at q24 intervals, started 24 h after 
the loading dose. This ibuprofen dosing regimen is as per the standard of care at our NICU  
 
Placebo (sterile water) q 6 hours x 12 doses 
 
Discontinue placebo after dose #12 if PDA closed. 
 
If infant is NPO; the subject will be withdrawn from the study. 
 
Pharmacy 
 
The pharmacist will randomly assign the subject to one treatment arm. Randomization to treatment arm 
will be performed by using randomly assigned, serially numbered envelopes. The population will be 
stratified to two subgroups based on gestational age GA ≤24 weeks or GA ≥ 25 weeks. The 
randomization will be performed after the subject has been assigned to one of the 2 subgroups. 
 
Medication storage 
 
The medication will be stored in a segregated area of the pharmacy designated for study medications. 
Intravenous  Ibuprofen preparation: 
Intravenous ibuprofen is available in a standard concentration of 10 mg/ml. This available standard 
concentration will not be further diluted. Intravenous ibuprofen will be dosed as described above.    
Patient specific doses will be drawn up by pharmacist and dispensed. 
 
Oral acetaminophen preparation 
 
Acetaminophen will be dispensed as a 160 mg/5 ml (32 mg/ml) solution.  Each dose will be calculated 


July 2018, rev 3 
 
Page 11 of 17 
and rounded to the nearest 0.01mi. Patient specific doses will be drawn up, labeled as study drug, and 
dispensed in an opaque syringe. 
 
Oral Placebo preparation 
 
Placebo will be sterile water without any added flavor or dextrose. Acetaminophen will be dye free, no 
added coloring agents will be used. The volume dispensed will be the same as the volume that would be 
dispensed if the subject is assigned to study drug.  Each dose will be labeled as study drug and dispensed 
in an opaque syringe. 
 
 
Table of medication volumes 
 
Acetaminophen (32 mg/ml) 
Placebo 
15 mg/kg 
Vol Dispensed Vol Dispensed 
4.5mg 
0.14ml 
0.14 ml 
5.25 mg 
0.16ml 
0.16ml 
6mg 
0.19 ml 
0.19 ml 
6.75 mg 
0.21ml 
0.21ml 
7.5 mg 
0.23ml 
0.23 ml 
8.25 mg 
0.26ml 
0.26 ml 
9mg 
0.28ml 
0.28 ml 
9.75 mg 
0.3ml 
0.3 ml 
10.5 mg 
0.33ml 
0.33 ml 
11.25 mg 
0.35ml 
0.35ml 
12 mg 
0.38ml 
0.38ml 
12.75 mg 
0.4ml 
0.4ml 
13.5 mg 
0.42 ml 
0.42ml 
14.25 mg 
0.45 ml 
0.45ml 
15 mg 
0.47ml 
0.47 ml 
 


July 2018, rev 3 
 
Page 12 of 17 
Study drugs will be monitored by the pharmacist and recorded on the medication dispensing 
record. 
 


July 2018, rev 3 
 
Page 13 of 17 
Rationale for acetaminophen dosage, schedule, and serum levels 
 
Acetaminophen is a commonly used drug in all ages. In newborns, it is commonly given for prevention or 
treatment of fever related to vaccinations. Although its use is safe in newborn infants, its pharmacokinetic 
characteristics are not well known. 
 
The table below (Table 1) shows a summary of published reports about preterm patients who received 
oral acetaminophen for ductal closure. After examining these reports, a conclusion can be made that oral 
administration of acetaminophen may be safe at a dose of 15 mg/kg every 6 hours for three to six days. 
None of these studies found any undesirable effect from the use of acetaminophen. Liver enzymes remain 
normal in all studies, except for the Dang, et al, study which did not report these values. In addition, 
acetaminophen seems to be useful in closing the PDA of preterm infants. Oral acetaminophen was 
associated with a 66% closure of the hemodynamically active PDAs (100 out of 152 infants experienced a 
closure of their PDA). 
 
Although acetaminophen, used for ductal closure, was not associated with any major complications, its 
pharmacokinetics in extremely low birth weight infants remain uncertain. This uncertainty warrants 
the monitoring of acetaminophen serum levels. 
 
Holding or stopping feeds for 1-2 days is a common occurrence in preterm infants.  Infants who are 
not able to tolerate enteral milk or meds at the beginning of the study will not be included in the 
study. However, for infants who have been feeding and were included in the study, if the clinical 
care team decides to hold their enteral feeds and meds, infant will be withdrawn from the study 
intervention. Management will be as per the standard practice in the NICU and will be at the discretion of 
attending neonatologists. . 
 
Table 1. Published Reports using Oral Acetaminophen for PDA Closure 
 
Authors/GA 
Mode/dose of 
Acetaminophen 
    
   N 
Duration 
(days) 
Closed 
C
l
o
Elevated 
LFT 
EI-Khuffash12014 
GA 26 weeks 
Oral 15/kg q6hr 
Oral 15/kg q6hr  
IV   15/kg q6hr 
N=5 
N=7 
N=9 
2 
7 
2-6 
0/5 
1/7 
5/9 
0 
Dang et al 2 2013 
GA 31weeks 
Oral 15/kg q6hr 
N=80 
3 
45/80 
Not 
mentioned 
OnceI et al3 2014 
GA 27 weeks 
Oral 15/kg q6hr 
N=40 
3 
29/40 
0 
Hammerman 2011 
GA 26-32 weeks 
Oral 15/kg q6hr 
N=5 
2-3 (some 7) 5/5 
0 
Jasaniet al 4 2013 
GA 26-32 weeks 
Oral15/kg q6hr 
N=6 
3 (some 6) 
6/6 
0 


July 2018, rev 3 
 
Page 14 of 17 
Ozdemiret  al5 2014 
GA 23-32 weeks 
Oral 15/kg q6hr 
N=7 
3 (some 7} 
5/7 
0 
Kesselet al6  2014 
GA 26-30 weeks 
Oral15/kg q6hr 
N=7 
3 (some 7) 
5/7 
0 
Nadir et al7 2014 
GA 24-27 weeks 
Oral15/kg q6hr 
N=7 
Up to 7 
5/7 
0 
References 
 
1. EI-Khuffash A, Jain A, Corcoran D, Shah PS, Hooper  CW, Brown N, Poole SD, Shelton 
El,Milne Gl,Reese J, McNamara PJ. Efficacy of paracetamol on patent ductus  arteriosus 
closure  may be dose dependent: evidence from  human  and murine studies. Pediatr Res. 
2014 Sep;76(3):238-44. 
 
2. Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol versus 
ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled 
trial.  PloS One. 2013 Nov 4;8(11):e77888 
 
3. Oncel MY, Yurttutan S, Erdeve 0, Uras N2, Altug N, Oguz SS, Canpolat FE, Oilmen U.Oral 
paracetamol versus oral ibuprofen in the management of patent ductus  arteriosus in 
preterm infants: a randomized controlled trial. J Pediatr. 2014 Mar;164(3):510-4. 
 
4. Jasani B, Kabra N, Nanavati RN. Oral paracetamol in treatment of closure of patent ductus  
arteriosus in preterm neonates. J Postgrad Med.  2013;59:312-314. doi:10.4103/0022-
3859.123164. 
 
5. Ozdemir  OM, Dogan M, Kucuktasci K, Ergin H,Sahin 0. Paracetamol therapy for patent 
ductus  arteriosus in premature infants: a chance before surgical ligation. 
PediatrCardiol.2014;35:276-279. 
 
6. Kessell, Waisman D, lavie-Nevo K, Golzman M, Lorber  A, Rotschild  A. Paracetamol 
effectiveness, safety and blood  level monitoring during patent ductus  arteriosus closure: a 
case series. J Matern Fetal Neonatal Med.  2014;27:1719-1721. 
 
7. Nadir E, Kassem E, Foldi S, Hochberg A, Feldman M. Paracetamol treatment of patent ductus 
arteriosus in preterm  infants. J Perinatol. 2014;34:748-749. 
 
 


July 2018, rev 3 
 
Page 15 of 17 
 
DATA AND SAFETY MONITORING PLAN (DSMP) 
 
Study title: Safety and efficacy of acetaminophen in extremely low birth infants used in addition 
to ibuprofen for ductal closure. 
 
Risk Classification of the study:  Greater than minimal risk, but presenting the prospect of direct 
benefit to the individual subject. 
 
Type of Research data/events to be monitored: 
 
The efficacy of acetaminophen will be monitored by echocardiogram, assessing the size of the 
lumen of the ductus arteriosus. Echocardiograms are standard procedures which are routinely used 
for the diagnoses and monitoring of PDA therapy in preterm infants. Drug safety factors will be 
assessed daily during the treatment. 
 
All blood and urine sample tests included in this study are routinely performed in preterm infants 
who are diagnosed or treated for a persistent patent ductus arteriosus, except for acetaminophen 
serum levels. 
 
In addition to serum liver enzymes and creatinine, two acetaminophen serum levels will be 
obtained during the study treatment; each consists of 0.2 ml of blood. 
 
Most of premature infants have umbilical arterial catheter in the first 2 weeks of life. Blood 
samples will be obtained directly from these catheters. In infants who do not have an indwelling 
catheter, blood sample will be obtained by a heel stick. 
 
Persons Responsible for Data Monitoring 
 
Gina Massey, RN and Ellen Dean, RN will monitor for any adverse event or unanticipated 
problems. In addition, independent data safety monitoring board (DSMB) will perform safety monitoring by 
running interim analyses. DSMB will be provided with deidentified blinded data.   Dr. Ariel Salas, Assistant 
Professor of Pediatrics, neonatology division, University of Alabama at Birmingham will serve as 
DSMB chair. He will be assisted by two other attending neonatologists. DSM B  will perform 3 interim 
analyses as indicated below. He will also give recommendations to continue or stop the trial based 
on the pre-specified criteria elaborated below. 
 
Reporting unanticipated problem, adverse events, protocol deviation or violation: 
 
Any unanticipated problem or adverse event that occurs during the study treatment or anytime  
during the follow-up period  (one week after the completion of therapy)  will be assessed by 
pharmacists, nurses, physicians caring for the infant, monitoring team, and hospital administrators. 
Mortality and life threatening morbidities will be evaluated as soon as possible (within 24 hours) 
by the monitoring team.  The monitoring team will notify parents immediately and notify the IRB 
within 5 business days. 
 
It is the responsibility of the monitoring team to decide if an event is a protocol deviation (does not affect 
safety or efficacy) or violation (deviation from the approved  IRB protocol or may  potentially affect  the 
infant).  Any protocol violation or deviation will be will be reported within 5 business days to the IRB. 
 
 
 


July 2018, rev 3 
 
Page 16 of 17 
Procedures and Time frames for communicating outcomes: 
 
Patient medical information (vital signs, respiratory support, fluid intake, output, medications, and 
blood test results) will be collected, entered in encrypted Excel files, and stored on password 
protected computers. Computers are kept in secure (C-WEB) area of the hospital. 
 
While adverse events will be investigated without any delay, all other patient data will be analyzed at 
25%, 50% and 75% completion of study population enrollment. Report to IRB will be sent after every 
DSMB meetings. The project is expected to last for about 4 years. 
 
Emergency actions: Unblinding- 
 
Pharmacists and laboratory staff are not blinded to the study. A root cause analysis will be performed 
after any adverse event. The monitoring team and pharmacists will evaluate if the event is related to 
the study treatment. If this is the case, the treatment will be shared with the clinical team and parents. 
 
Withdrawal subject from the study- 
 
The study intervention will be stopped if any of the following occur: 
 
a. Elevation of liver enzymes AST or ALT > 3 fold baseline values. These results will be 
available for the team caring for the baby 
b. Acetaminophen trough serum levels> 30 microgram/ml (mg/L) will be called to the 
nursery as critical value. 
c. AKI stage 2 or greater (as defined above) 
d. gastrointestinal bleeding 
e. Necrotizing enterocolitis 
f. NPO 
 
Rules for stopping the study: 
 
DSMB will meet and analyze the data after the enrollment of 25%. 50% and 75% of study population 
and will decide about to continuation/discontinuation of the study. 
 
The study will be stopped as per DSMB recommendations if following pre-specified criteria are met 
 
1)  Haybittle-Peto boundary will be used for stopping the study based on the efficiency of treatment 
arm 
 
No. interim analyses 
Interim analyses 
P value boundary 
3 
1 
0.001 
2 
0.001 
3 (final) 
0.05 
 
2)  Pocock boundary will be used for adverse event or futility monitoring (p value 0.0221), which 
is same at each interim analysis. Interim analyses will be performed more often, every month, for 


July 2018, rev 3 
 
Page 17 of 17 
futility testing. 
Precautions for maintaining data integrity: 
 
The goal of the principal investigator, other investigators and team monitors is to find the best and 
safest treatment for sick preterm infants. No financial or other non-monetary gain will be obtained 
by any of the investigators or monitors. 
 
All collected data will remain confidential even after the study is completed. It is also kept secured 
as detailed above. However, although data will be safe from unauthorized access, it will still be 
accessible to authorized users (monitor team and principal investigator). In addition, data will be 
backed up weekly in addition to keeping a copy with each of the monitoring team members. 
 
Secondary data analysis: 
 
Persistent PDA among extremely low birth weight infants is common. Incidence of persistent PDA 
is inversely related to gestational age and severity of respiratory distress syndrome. Late postnatal 
corticosteroids use has shown to decrease the composite outcome of death or BPD among high risk 
preterm infants by attenuating the pulmonary inflammation and improving the lung compliance. 
Hence, late postnatal corticosteroid might influence the hemodynamics of PDA among extremely 
preterm infants and enable extubation by improving lung compliance despite of persistent PDA. 
However prospective data on the influence of corticosteroid on the natural course of PDA among 
ELBWI is lacking. Data collected for this RCT will be used to analyze natural course of PDA among 
preterm infants  who are treated with  late postnatal corticosteroids. 
 
 
As PI of this research study, I endorse the information in this DSMP for I acknowledge that,as a PI,I am 
responsible for implementation of the DSMP by all members of the research team. 
 
 
 
 
 
 
 
Investigator Signature   
 
 
 
 
 
 
 
Date