Comparison of Oral and Intravenous Ibuprofen for PDA Treatment in Premature Infants

Study Overview
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Brief Summary
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Background: Patent ductus arteriosus (PDA) continues to be one of the most common problems in premature infants. Pharmacological closure of PDA with intravenous (IV) indomethacin was first reported in 1976, however, concern remains regarding the safety of indomethacin, which affects renal, GI and cerebral perfusion and may lead to complications such as transient or permanent renal dysfunction, NEC, GI hemorrhage, and reduced cerebral oxygenation. Recently, IV ibuprofen has been shown to be effective for the closure of patent ductus arteriosus in premature infants, without reducing mesenteric, renal, or cerebral blood flow. We have developed the echocardiographic PDA flow pattern as a guide for PDA treatment, fewer doses of drugs were needed to achieve acceptable closing rates. We have also reported that IV ibuprofen is as effective as IV indometacin for the PDA treatment in extremely premature infants, without increasing the incidence of complications in a randomised controlled trial. Several studies reported that oral ibuprofen may be effective for PDA treatment. To date there is no firm conclusion as to the efficacy and safety of oral ibuprofen compared with IV ibuprofen for PDA closure in extremely premature infants. Objective: Since the efficacy of pharmacological closure of PDA is related to gestational age, and extremely premature infants carry the highest rate of mortality and morbidity. We intend to conduct a randomized controlled trial to compare oral and intravenous ibuprofen for treatment of PDA in this high-risk population of extremely premature infants. Methods: Extremely premature infants (gestational age < 28 weeks) admit to the NICU will be eligible for enrollment. Informed parental consent will be obtained according to the Institutional Review Board's instructions. Extremely premature infants with respiratory distress syndrome (RDS) and PDA confirmed by echocardiography will be randomly assigned to receive either oral or IV ibuprofen. The subsequent doses of ibuprofen are also determined according to our specific echocardiographic PDA flow patterns at intervals of once every 24 hours from the last dose. The dosage of oral or ibuprofen is 10 mg/kg (1 ml) and then 5 mg/kg at 24-hour intervals as indicated by echocardiographic PDA flow pattern. Sample Size Calculation and Length of the Study Period: About 50-60 extremely premature infants will be admitted to our NICU each year. To prove with McNemar's Test at a one-sided significance level of 5% and a power of 90% that using oral ibuprofen instead of IV ibuprofen results in comparable PDA closure rates, only 31 extremely premature infants with RDS and PDA have to be enrolled. Allowing for attrition and exclusion from the final study groups, the length of the study period will be safe to set to 2 years. Expected Results: We expect to determine whether oral ibuprofen is effective and safe in inducing PDA closure in extremely premature infants and to compare the complications between infants treated with oral ibuprofen and those with IV ibuprofen.

Official Title
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Comparison of Oral and Intravenous Ibuprofen for Treatment of Patent Ductus Arteriosus in Extremely Premature Infants: A Randomized Controlled Trial

Conditions
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Extremely Premature Infants, PDA, Oral Ibuprofen, IV Ibuprofen

Intervention / Treatment
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* Drug: iv ibuprofen
* Drug: oral ibuprofen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: premature infants gestational age < 28 weeks, respiratory distress syndrome requiring assisted ventilation, a PDA without other cardiac anomalies confirmed by echocardiography within 24 hours after birth, Exclusion Criteria: severe congenital anomalies or lethal cardiopulmonary conditions, and informed consent could be obtained from parents

Ages Eligible for Study
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Minimum Age: 3 Hours
Maximum Age: 24 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: IV ibuprofen<br>The first dose of either oral or IV ibuprofen will be given at the time the patient is randomized.The subsequent doses of indometacin or ibuprofen are also determined according to the echocardiographic PDA flow patterns at intervals of once every 24 hours from the last dose. The dosage of both oral ibuprofen (Ibuprofen suspension, 20 mg/ml, Yung Shing Co., Taiwan) and IV ibuprofen (PedeaR 20 mg/ml, developed by Orphan Europe and approved by the EMEA) are an initial dose of 10 mg/kg and then 5 mg/kg at 24-hour intervals as indicated by PDA flow pattern. | Drug: iv ibuprofen<br> <br> |
| Active Comparator: Oral ibuprofen<br> | Drug: oral ibuprofen<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome is to ascertain whether oral ibuprofen is effective and safe in inducing PDA closure in extremely premature infants. | Number of extremely premature infants with PDA closed or Adverse Events as a Measure of efficiency and safety. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A secondary objective is to compare the complications between infants treated with oral ibuprofen and those treated with IV ibuprofen. | Number of extremely premature infants in each group with PDA closed or Adverse Events as a Measure of efficiency and safety. | 1 month |