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

• Sponsor: University of South Alabama (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03701074
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arms: 2
• Actual Duration (Months): 23.6
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Patent Ductus Arteriosus; Preterm Infant; Bronchopulmonary Dysplasia	Drug: Ibuprofen and acetaminophen; Drug: Ibuprofen and placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Dec 15, 2018
• Actual Primary Completion Date: Oct 30, 2020
• Actual Study Completion Date: Dec 2, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ibuprofen and acetaminophen arm (intervention arm) 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).	Drug: Ibuprofen and acetaminophen; Intravenous ibuprofen given concomitantly with oral acetaminophen
Active Comparator: ibuprofen and placebo arm (control arm) 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.	Drug: Ibuprofen and placebo; Intravenous ibuprofen given concomitantly with oral placebo

Outcome Measures

Primary Outcome Measures

1. Ductus Arteriosus Closure/Constriction Rate [24-48 hours after the completion of study intervention]

   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

Secondary Outcome Measures

1. Echocardiographic Patent Ductus Arteriosus Parameters Before and After the Study Intervention [24-48 hours after the completion of study intervention]

2. Ventilatory Settings Before and After the Study Intervention [24-48 hours after the completion of study intervention]

3. Rate of Liver Injury [24-48 hours after the completion of study intervention]

   liver enzymes before and after the study intervention

4. Rate of Renal Injury [24-48 hours after the completion of study intervention]

   Blood urea nitrogen (BUN) and serum creatinine before and after the study intervention

5. Rate of Hematological Adverse Events [24-48 hours after the completion of study intervention]

   Hematocrit and platelets before and after the study intervention

6. Total Number of Days of Mechanical Ventilation [from randomization until discharge/40 weeks post menstrual age]

7. Total Number of Days of Need for Supplemental Oxygen [from randomization until discharge/40 weeks post menstrual age]

8. Duration of Noninvasive Ventilation [from randomization until discharge/40 weeks post menstrual age]

9. Rate of Persistence of Ductus-needing Pharmacological Treatment [from randomization until discharge/40 weeks post menstrual age]

10. Rate of Surgical Ligation of PDA [from randomization until discharge/40 weeks post menstrual age]

11. Rate of Bronchopulmonary Dysplasia [at 36 weeks post menstrual age]

12. Percentage of Infants Requiring Home Oxygen Therapy [at discharge/40 weeks post menstrual age]

13. Death Before Discharge [until discharge/40 weeks post menstrual age]

14. Time to Achieve Full Enteral Feeding [from birth until discharge/40 weeks post menstrual age]

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

15. Days on Total Parenteral Nutrition [from birth until discharge/40 weeks post menstrual age]

16. Retinopathy of Prematurity [from birth until discharge/40 weeks post menstrual age]

17. Rate of Spontaneous Intestinal Perforation [from randomization until discharge/40 weeks post menstrual age]

18. Rate of Necrotizing Enterocolitis [from randomization until discharge/40 weeks post menstrual age]

19. Rate of Gastrointestinal Hemorrhage [from randomization until discharge/40 weeks post menstrual age]

20. Rate of Late Onset Sepsis [from randomization until discharge/40 weeks post menstrual age]

21. Length of Hospital Stay [from birth until discharge/40 weeks post menstrual age]

22. Rate of Periventricular Leukomalacia [from randomization until discharge/40 weeks post menstrual age]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Days to 21 Days
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

5. Ductus size ≥ 1.5 mm

6. Maximum flow velocity through the ductus ≤ 2 m/s

7. Left atrium to aorta ratio ≥ 1.4

8. Wide pulse pressure

9. B-type natriuretic peptide (BNP)

10. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of South Alabama	Mobile	Alabama	United States	36607

Sponsors and Collaborators

• University of South Alabama

Investigators

• Study Director: Fabien Eyal, MD, University of South Alabama

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 7, 2018

More Information

Publications

None provided.

• Responsible Party: Ramachandra Bhat, Assistant Professor, University of South Alabama
• ClinicalTrials.gov Identifier: NCT03701074
• Other Study ID Numbers: 15-081/730216-8
• First Posted: Oct 9, 2018
• Last Update Posted: May 11, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ramachandra Bhat, Assistant Professor, University of South Alabama: patent ductus arteriosus; acetaminophen; ibuprofen; bronchopulmonary dysplasia; mechanical ventilation
• Additional relevant MeSH terms: Bronchopulmonary Dysplasia; Premature Birth; Ductus Arteriosus, Patent; Acetaminophen; Ibuprofen

Study Results

Participant Flow

Recruitment Details	Overall screening for the study enrollment started 12/15/2018. Screening was continued until 10/30/2020. The study was conducted at the Neonatal Intensive Care Unit

Arm/Group Title	Ibuprofen and Acetaminophen Arm (Intervention Arm)	Ibuprofen and Placebo Arm (Control Arm)
Arm/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). Ibuprofen and acetaminophen: Intravenous ibuprofen given concomitantly with oral acetaminophen	ibuprofen and placebo 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. Ibuprofen and placebo: Intravenous ibuprofen given concomitantly with oral placebo
Period Title: Overall Study
STARTED	1	0
COMPLETED	0	0
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Ibuprofen and Acetaminophen Arm (Intervention Arm)	Ibuprofen and Placebo Arm (Control Arm)	Total
Arm/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). Ibuprofen and acetaminophen: Intravenous ibuprofen given concomitantly with oral acetaminophen	ibuprofen and placebo 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. Ibuprofen and placebo: Intravenous ibuprofen given concomitantly with oral placebo	Total of all reporting groups
Overall Participants	1	0	1
Age (Count of Participants)
<=18 years	1 100%	0 NaN	1 100%
Between 18 and 65 years	0 0%	0 NaN	0 0%
>=65 years	0 0%	0 NaN	0 0%
Sex: Female, Male (Count of Participants)
Female	1 100%	0 NaN	1 100%
Male	0 0%	0 NaN	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 NaN
Asian	0 0%	0 NaN
Native Hawaiian or Other Pacific Islander	0 0%	0 NaN
Black or African American	0 0%	0 NaN
White	1 100%	1 Infinity
More than one race	0 0%	0 NaN
Unknown or Not Reported	0 0%	0 NaN
Region of Enrollment (participants) [Number]
United States	1 100%	1 Infinity
PDA size (mm) [Number]
Number [mm]	1.5	1.5

Outcome Measures

1. Primary Outcome

Title	Ductus Arteriosus Closure/Constriction Rate
Description	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

Outcome Measure Data

Analysis Population Description

None were enrolled for the control arm

Arm/Group Title	Ibuprofen and Acetaminophen Arm (Intervention Arm)	Ibuprofen and Placebo Arm (Control Arm)
Arm/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). Ibuprofen and acetaminophen: Intravenous ibuprofen given concomitantly with oral acetaminophen	ibuprofen and placebo 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. Ibuprofen and placebo: Intravenous ibuprofen given concomitantly with oral placebo
Measure Participants	1	0
Count of Participants [Participants]	0 0%	0 NaN

2. Secondary Outcome

Title	Echocardiographic Patent Ductus Arteriosus Parameters Before and After the Study Intervention
Time Frame	24-48 hours after the completion of study intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Ventilatory Settings Before and After the Study Intervention
Time Frame	24-48 hours after the completion of study intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Rate of Liver Injury
Description	liver enzymes before and after the study intervention
Time Frame	24-48 hours after the completion of study intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Rate of Renal Injury
Description	Blood urea nitrogen (BUN) and serum creatinine before and after the study intervention
Time Frame	24-48 hours after the completion of study intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Rate of Hematological Adverse Events
Description	Hematocrit and platelets before and after the study intervention
Time Frame	24-48 hours after the completion of study intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Total Number of Days of Mechanical Ventilation
Time Frame	from randomization until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Total Number of Days of Need for Supplemental Oxygen
Time Frame	from randomization until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Duration of Noninvasive Ventilation
Time Frame	from randomization until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Rate of Persistence of Ductus-needing Pharmacological Treatment
Time Frame	from randomization until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Rate of Surgical Ligation of PDA
Time Frame	from randomization until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Rate of Bronchopulmonary Dysplasia
Time Frame	at 36 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Percentage of Infants Requiring Home Oxygen Therapy
Time Frame	at discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Death Before Discharge
Time Frame	until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Time to Achieve Full Enteral Feeding
Description	Time to achieve 120 ml/kg/day of enteral feeding
Time Frame	from birth until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Secondary Outcome

Title	Days on Total Parenteral Nutrition
Time Frame	from birth until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Secondary Outcome

Title	Retinopathy of Prematurity
Time Frame	from birth until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Secondary Outcome

Title	Rate of Spontaneous Intestinal Perforation
Time Frame	from randomization until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Secondary Outcome

Title	Rate of Necrotizing Enterocolitis
Time Frame	from randomization until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

20. Secondary Outcome

Title	Rate of Gastrointestinal Hemorrhage
Time Frame	from randomization until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

21. Secondary Outcome

Title	Rate of Late Onset Sepsis
Time Frame	from randomization until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

22. Secondary Outcome

Title	Length of Hospital Stay
Time Frame	from birth until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

23. Secondary Outcome

Title	Rate of Periventricular Leukomalacia
Time Frame	from randomization until discharge/40 weeks post menstrual age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	4 months
Adverse Event Reporting Description	None were enrolled into control arm, Therefore, number infants at risk for adverse events under the control arm are zero
Arm/Group Title	Ibuprofen and Acetaminophen Arm (Intervention Arm)		Ibuprofen and Placebo Arm (Control Arm)
Arm/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). Ibuprofen and acetaminophen: Intravenous ibuprofen given concomitantly with oral acetaminophen		ibuprofen and placebo 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. Ibuprofen and placebo: Intravenous ibuprofen given concomitantly with oral placebo
All Cause Mortality
	Ibuprofen and Acetaminophen Arm (Intervention Arm)		Ibuprofen and Placebo Arm (Control Arm)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)
Serious Adverse Events
	Ibuprofen and Acetaminophen Arm (Intervention Arm)		Ibuprofen and Placebo Arm (Control Arm)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Ibuprofen and Acetaminophen Arm (Intervention Arm)		Ibuprofen and Placebo Arm (Control Arm)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)
Renal and urinary disorders
Biochemical evidence of acute kidney injury with preserved renal function, probably nor related to i	1/1 (100%)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.