No Treatment Versus Oral Ibuprofen Treatment for Patent Ductus Arteriosus in Preterm Infants

Efficacy and Safety of No Treatment Compared With Oral Ibuprofen Treatment for Patent Ductus Arteriosus in Preterm Infants: a Randomized, Double-blind, Placebo-controlled, Non-inferiority Clinical Trial

The purpose of this study is to evaluate the efficacy and safety of no treatment compared with ibuprofen treatment for patent ductus arteriosus in preterm infants. The study hypothesis is that no treatment is not inferior to oral ibuprofen treatment in preterm infants. (non-inferiority study)

Study Overview

• Status: Completed
• Conditions: Bronchopulmonary Dysplasia (BPD)
• Intervention / Treatment: Drug: Oral ibuprofen; Drug: Normal saline

Detailed Description

This study is a randomized, double-blind, placebo-controlled, non-inferiority clinical trial.

• Study Type: Interventional
• Enrollment (Actual): 142
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 days to 2 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. gestational age of 30 weeks or less or birth weight of 1250 g or less
2. born in Samsung Medical Center
3. confirmed to have hemodynamically significant patent ductus arteriosus (PDA) during day of life (DOL) 5 to 14

4. Definition of hemodynamically significant PDA: ductal size ≥ 1.5 mm with left-to-right shunt (or bidirectional shunt with dominant left-to-right blood flow) on the initial echocardiography plus at least one of clinical criteria.

   • Clinical criteria

     • Respiratory signs, including tachypnea, chest retraction, increased respiratory support, unable to wean respiratory support
     • Physical signs, including a murmur, hyperdynamic precordium or bounding pulses
     • Blood pressure problems, including decreased mean or diastolic pressure or increased pulse pressure
     • Signs of congestive heart failure, including cardiomegaly, hepatomegaly or pulmonary congestion

Exclusion Criteria:

• Mortality within the first 48 hours of life
• Ductal size < 1.5 mm on the initial echocardiography
• Right-to-left shunt or bidirectional shunting with dominant right-to-left shunt through PDA
• congenital anomaly
• bilateral intraventricular hemorrhage of grade 4
• contraindication of ibuprofen (bleeding diasthesis, platelet count 10,000/mm3 or less, serum creatinine 2.0 mg/dL or greater, necrotizing enterocolitis stage 2 or greater

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Oral ibuprofen; Initial dose of 10 mg/kg of oral ibuprofen, followed by 2 doses of 5 mg/kg 24 and 48 h later	Drug: Oral ibuprofen; Initial dose of 10 mg/kg of oral ibuprofen, followed by two doses of 5 mg/kg 24 and 48 hours later; Other Names: Brufen® syrup, Samil pharm. Co., Ltd.
Placebo Comparator: Normal saline; Initial dose of normal saline followed by second and third dose 24 and 48 hours later, at equal volume to ibuprofen arm	Drug: Normal saline; Initial dose of normal saline followed by second and third dose 24 and 48 hours later, at equal volume to ibuprofen arm; Other Names: Sodium chloride, Huons. Inc.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of moderate to severe bronchopulmonary dysplasia (BPD) or mortality at 36 weeks postmenstrual age (PMA)	36 weeks PMA

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of moderate to severe BPD	36 weeks PMA
Incidence of oxygen dependency at 40 weeks PMA	40 weeks PMA
Mortality rate	28-days since birth and 36 weeks PMA
incidence of intraventricular hemorrhage (grade 3 or greater)	28-days since birth
Incidence of retinopathy of prematurity (stage III or greater)	40 weeks PMA (± 2 weeks)
Incidence of necrotizing enterocolitis (stage 2b or greater)	40 weeks PMA (± 2 weeks)
Duration of PDA	40 weeks PMA (± 2 weeks)
Duration of intubation	36 weeks PMA
Duration of nasal continuous positive airway pressure (NCPAP) treatment	40 weeks PMA (± 2 weeks)
Cumulative duration of oxygen use	40 weeks PMA (± 2 weeks)
Incidence of adverse events	participants will be followed for the duration of hospital stay, an expected average of 12 weeks
Growth velocity	40 weeks PMA (± 2 weeks)

Collaborators and Investigators

• Sponsor: Samsung Medical Center
• Investigators: Principal Investigator: Se In Sung, M.D., Samsung Medical Center

Publications and helpful links

General Publications

• Sung SI, Lee MH, Ahn SY, Chang YS, Park WS. Effect of Nonintervention vs Oral Ibuprofen in Patent Ductus Arteriosus in Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2020 Aug 1;174(8):755-763. doi: 10.1001/jamapediatrics.2020.1447.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): August 1, 2019
• Study Completion (Actual): August 1, 2019

Study Registration Dates

• First Submitted: April 23, 2014
• First Submitted That Met QC Criteria: April 29, 2014
• First Posted (Estimate): May 1, 2014

Study Record Updates

• Last Update Posted (Actual): January 13, 2020
• Last Update Submitted That Met QC Criteria: January 9, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Bronchopulmonary dysplasia; Ibuprofen; Patent ductus arteriosus
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Congenital Abnormalities; Infant, Newborn, Diseases; Lung Injury; Heart Defects, Congenital; Cardiovascular Abnormalities; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Bronchopulmonary Dysplasia; Ductus Arteriosus, Patent; 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: 2013-07-129

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No