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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

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ClinicalTrials.gov Identifier: NCT03701074
Recruitment Status : Recruiting
First Posted : October 9, 2018
Last Update Posted : January 4, 2019
Sponsor:
Information provided by (Responsible Party):
Ramachandra Bhat, University of South Alabama

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 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 : December 15, 2018
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : December 2020


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




Primary Outcome Measures :
  1. ductus arteriosus closure/constriction rate [ Time Frame: 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 [ Time Frame: 24-48 hours after the completion of study intervention ]
  2. Ventilatory settings before and after the study intervention [ Time Frame: 24-48 hours after the completion of study intervention ]
  3. rate of liver injury [ Time Frame: 24-48 hours after the completion of study intervention ]
    liver enzymes before and after the study intervention

  4. rate of renal injury [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: from randomization until discharge/40 weeks post menstrual age ]
  7. Total number of days of need for supplemental oxygen [ Time Frame: from randomization until discharge/40 weeks post menstrual age ]
  8. Duration of noninvasive ventilation [ Time Frame: from randomization until discharge/40 weeks post menstrual age ]
  9. rate of persistence of ductus-needing pharmacological treatment [ Time Frame: from randomization until discharge/40 weeks post menstrual age ]
  10. rate of surgical ligation of PDA [ Time Frame: from randomization until discharge/40 weeks post menstrual age ]
  11. rate of Bronchopulmonary dysplasia [ Time Frame: at 36 weeks post menstrual age ]
  12. Percentage of infants requiring home Oxygen therapy [ Time Frame: at discharge/40 weeks post menstrual age ]
  13. Death before discharge [ Time Frame: until discharge/40 weeks post menstrual age ]
  14. Time to achieve full enteral feeding [ Time Frame: 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 [ Time Frame: from birth until discharge/40 weeks post menstrual age ]
  16. Retinopathy of prematurity [ Time Frame: from birth until discharge/40 weeks post menstrual age ]
  17. rate of spontaneous intestinal perforation [ Time Frame: from randomization until discharge/40 weeks post menstrual age ]
  18. rate of Necrotizing enterocolitis [ Time Frame: from randomization until discharge/40 weeks post menstrual age ]
  19. rate of gastrointestinal hemorrhage [ Time Frame: from randomization until discharge/40 weeks post menstrual age ]
  20. rate of late onset sepsis [ Time Frame: from randomization until discharge/40 weeks post menstrual age ]
  21. Length of hospital stay [ Time Frame: from birth until discharge/40 weeks post menstrual age ]
  22. rate of periventricular leukomalacia [ Time Frame: from randomization until discharge/40 weeks post menstrual age ]


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Ages Eligible for Study:   up to 21 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03701074


Contacts
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Contact: Ramachandra Bhat, MD 2514151055 rbhat@health.southalabama.edu
Contact: Fabien Eyal, MD 2514151055 feyal@health.southalabama.edu

Locations
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United States, Alabama
University of South Alabama Recruiting
Mobile, Alabama, United States, 36607
Contact: Ramachandra Bhat, MD    251-415-1055    rbhat@health.southalabama.edu   
Sponsors and Collaborators
University of South Alabama
Investigators
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Study Director: Fabien Eyal, MD University of South Alabama

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Responsible Party: Ramachandra Bhat, Assistant Professor, University of South Alabama
ClinicalTrials.gov Identifier: NCT03701074     History of Changes
Other Study ID Numbers: 15-081/730216-8
First Posted: October 9, 2018    Key Record Dates
Last Update Posted: January 4, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ramachandra Bhat, University of South Alabama:
patent ductus arteriosus
acetaminophen
ibuprofen
bronchopulmonary dysplasia
mechanical ventilation
Additional relevant MeSH terms:
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Ibuprofen
Bronchopulmonary Dysplasia
Premature Birth
Ductus Arteriosus, Patent
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Ventilator-Induced Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Infant, Premature, Diseases
Infant, Newborn, Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities
Acetaminophen
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors