Oral Ibuprofen Versus Placebo in Treatment of Patent Ductus Arteriosus (PDA)in Preterm Infants

Oral Ibuprofen Versus Placebo in Management of Patent Ductus Arteriosus in Preterm Infants: A Double Blind, Randomized Control Trial

The management options of Patent Ductus Arteriosus are still controversial and differ between centers. Recently, conservative management has been gaining interest as the evidence of benefit from medical treatment in terms of mortality and morbidity is lacking.

This study will compare oral ibuprofen (the standard treatment) with the conservative treatment, in terms of ductal closure and morbidity and mortality at discharge in preterm neonates less than 34 weeks.

Study Overview

• Status: Completed
• Conditions: Patent Ductus Arteriosus After Premature Birth; Patent Ductus Arteriosus Conservative Management
• Intervention / Treatment: Drug: Ibuprofen oral suspension; Drug: Placebo

Detailed Description

A double-blinded, randomized, placebo-control non-inferiority trial was conducted in the neonatal intensive care unit (NICU) of Ain Shams University children's hospital, Cairo, Egypt.

Informed consent was taken from the parents or legal guardians before enrolment, after fully explaining to them the nature of the study. The approval of the Research Ethics Committee at Ain Shams University was also obtained.

All preterm neonates less than 34 weeks were assessed in the first 48 hours by clinical and echocardiographic examination by a cardiologist to detect PDA and exclude any congenital heart disease.

All neonates meeting the inclusion criteria will be randomized into one of two groups:

Medical treatment group and Placebo group. Targeted neonatal Echo was repeated after 5 days of the start of medical treatment by a neonatologist or a cardiologist to assess PDA closure.

After 7 days of intervention, open-label is offered to all patients with the option of another course for patients in the medical treatment group and Rescue therapy in the Placebo group.

The short-term morbidity is documented.

Withdrawal and replacement of individual subjects:

• The attending physician can decide to withdraw a subject from the study for urgent medical reasons. If they wish, parents or caregivers can leave the study at any time for any reason.
• Infants who are withdrawn from the study will be managed according to NICU Protocols.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Faculty of Medicine Ain shams University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 1 week (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Gestational age ≤ 34 weeks
• PDA Size > 1.5 mm and predominantly left-to-right shunt
• One of the following:
• Signs of Pulmonary overflow: Left atrium/Aortic diameter ratio (LA/Ao), Left Ventricular End Diastolic Diameter (LVEDD).
• Signs of Systemic Hypo perfusion: Absent or Reversed diastolic flow in the aorta, celiac/mesenteric, or Anterior Cerebral Artery (ACA)/ Middle Cerebral Artery (MCA)

Exclusion Criteria:

• Chromosomal anomaly
• Congenital heart defect, other than PDA and/or patent foramen ovale
• Congenital or acquired gastrointestinal anomaly
• Previous episodes of Necrotizing enterocolitis (NEC) or intestinal perforation
• Active bleeding, especially intracranial or gastrointestinal hemorrhage
• Contraindications to the use of ibuprofen

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Medical treatment Group; 40 preterm neonates will receive Ibuprofen oral suspension	Drug: Ibuprofen oral suspension; The medical treatment group will receive oral Ibuprofen with conservative therapy in the form of fluid restriction, Positive End Expiratory Pressure (PEEP), and/or diuretics An additional course of Ibuprofen may be offered if there is: Moderate/Severe PDA on Echocardiography; Prolonged ventilation or Increased ventilatory setting; Prolonged use of inotropes or vasopressors or escalating doseAnother form of treatment may be offered if the patient developed side effects from Ibuprofen; Other Names: Active treatment
Placebo Comparator: Placebo Group; 40 preterm neonates will receive oral placebo	Drug: Placebo; Placebo Group will receive Oral Placebo and Conservative therapy in the form of fluid restriction, PEEP, and/or diuretics An Open-label option might be offered if there are concerns by attending physicians over the poor patient condition that might be attributed to persistent PDA: Prolonged Ventilation or Escalating Ventilatory Setting; Prolonged Use Of Inotropes or Vasopressors or escalation of Doses Rescue therapy in the form of a course of oral ibuprofen may be offered: After 5 days of recruitment; Moderate/Severe PDA on Echocardiography; Prolonged ventilation or Increased ventilatory setting; Prolonged use of inotropes or vasopressors or escalating dose - Another form of treatment may be offered if the patient developed side effects from Ibuprofen; Other Names: Conservative

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of PDA Closure by Echocardiography	Compare the incidence of PDA closure assessed by Echocardiography during hospitalization between the two groups	Hospital discharge (approximately 3 months unless death occurs first)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of death during hospitalization	Compare the incidence of death during hospitalization between the two groups	Hospital discharge (approximately 3 months unless death occurs first)
Incidence of Necrotizing Enterocolitis (NEC)	Compare the incidence of NEC during hospitalization between the two groups by Bell's staging	Hospital discharge (approximately 3 months unless death occurs first)
Incidence of Bronchopulmonary dysplasia (BPD)	Compare the Incidence of BPD (needing supplemental oxygen at 28 days of life) during hospitalization between the two groups	Hospital discharge (approximately 3 months unless death occurs first)
Incidence of Sepsis	Compare the Incidence of sepsis during hospitalization between the two groups by positive blood culture.	Hospital discharge (approximately 3 months unless death occurs first)
Incidence of Intraventricular hemorrhage (IVH)	Compare the Incidence of IVH during hospitalization between the two groups by transcranial ultrasound	Hospital discharge (approximately 3 months unless death occurs first)

Collaborators and Investigators

• Sponsor: Nada Youssef
• Investigators: Principal Investigator: Nada H Youssef, ain shams University

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2021
• Primary Completion (Actual): August 15, 2022
• Study Completion (Actual): September 1, 2022

Study Registration Dates

• First Submitted: August 2, 2022
• First Submitted That Met QC Criteria: August 7, 2022
• First Posted (Actual): August 9, 2022

Study Record Updates

• Last Update Posted (Estimate): February 28, 2023
• Last Update Submitted That Met QC Criteria: February 25, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Heart Defects, Congenital; Cardiovascular Abnormalities; Premature Birth; 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: MD 96 2020

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