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

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

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.

Study Overview

• Status: Unknown
• Conditions: PDA; Extremely Premature Infants; Oral Ibuprofen; IV Ibuprofen
• Intervention / Treatment: Drug: iv ibuprofen; Drug: oral ibuprofen

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Bai-Horng Su, MD, PhD; Phone Number: 2061 886-4-22052121; Email: bais@ms49.hinet.net

Study Locations

• Taiwan
  • Taichung, Taiwan, 404
    • Recruiting
    • China Medical University Hospital
    • Principal Investigator: Bai-Horng Su, MD, PhD
    • Contact: Bai-Horng Su, MD, PhD; Phone Number: 2531 886-4-22052121; Email: bais@ms49.hinet.net
    • Sub-Investigator: Ming-Shia Lin, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 hours to 1 day (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: IV ibuprofen; 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
Active Comparator: Oral ibuprofen	Drug: oral ibuprofen

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: China Medical University Hospital
• Investigators: Study Chair: Bai-Horng Su, MD, PhD, China Medical University Hospital,Taiwan

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Anticipated): June 1, 2012
• Study Completion (Anticipated): June 1, 2012

Study Registration Dates

• First Submitted: June 20, 2010
• First Submitted That Met QC Criteria: June 22, 2010
• First Posted (Estimate): June 23, 2010

Study Record Updates

• Last Update Posted (Estimate): June 23, 2010
• Last Update Submitted That Met QC Criteria: June 22, 2010
• Last Verified: June 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ibuprofen
• Other Study ID Numbers: DMR-99; DMR-98 (Other Grant/Funding Number: China Medical University Hospital)