Early Treatment Versus Expectant Management of PDA in Preterm Infants

Randomized Non-inferiority Trial of Early Treatment Versus Expectant Management of Patent Ductus Arteriosus in Preterm Infants

Patent ductus arteriosus (PDA) in very preterm newborns is associated with severe neonatal mor-bidity: intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), necrotizing en-terocolitis (NEC), retinopathy of prematurity (ROP). Existing methods of management PDA do not reduce the incidence of these diseases. The efficacy of cyclooxygenase inhibitors (COX) which are currently the standard of treatment in extreme preterm infants is about 70-80%. COX inhibitors have significant side effects. On the other hand, surgical ligation of the ductus arteriosus is associated with deterioration due to cardio-pulmonary problems and long-term complications. Paracetamol has been proposed for treatment of hemodynamically significant PDA because it has a different mecha-nism of action compared with COX inhibitors and a better safety profile.

Recently, expectant approach has becoming more popular, although there is not enough evidence to support it.

The objective of this study is to investigate whether in preterm infants, born at a GA less than 32 weeks, with a PDA (diameter > 1.5 mm) at a postnatal age of < 72 h, an expectant management is non-inferior to early treatment with regard to the composite of mortality and/or severe morbidity.

Study Overview

• Status: Completed
• Conditions: Patent Ductus Arteriosus
• Intervention / Treatment: Drug: Ibuprofen; Drug: Paracetamol; Other: Expectant Management

• Study Type: Interventional
• Enrollment (Actual): 208
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Ukraine
  • Lviv, Ukraine, 79010
    • Lviv National Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Gestational age < 32 weeks
• Birthweight <1500 g
• Age less than 72 hours
• PDA diameter > 1.5 mm
• Signed informed consent obtained from both parents

Exclusion Criteria:

• Birthweight ≥ 1500 g and/or gestation age ≥ 32 weeks
• Lack of informed consent of the parents
• Congenital heart defect, other than PDA and/or patent foramen ovale (PFO)
• The presence of a clinically apparent hemorrhagic syndrome
• Any intraventricular hemorrhage (IVH) in the first 48 hours or IVH grade 3-4
• A platelet count of < 50,000/mm3
• A serum creatinine concentration of > 110 μmol/L
• Oliguria <1 ml/kg/h
• Suspected/apparent NEC
• Suspected/apparent lung hypoplasia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rectal ibuprofen; Early treatment of PDA that starts within the first 3 days of life using rectal ibuprofen q24h for 3 days, dosages: 20 mg/kg + 10 mg/kg + 10 mg/kg	Drug: Ibuprofen; In the medical treatment arm the in-tention is to close the ductus arteriosus.; Other Names: Cyclooxygenase Inhibitor
Active Comparator: Intravenous paracetamol; Early treatment of PDA that starts within the first 3 days of life using intravenous paraceta-mol 15 mg/kg q6h for 3 days	Drug: Paracetamol; In the medical treatment arm the in-tention is to close the ductus arteriosus.; Other Names: Infulgan, Acetaminophen
Sham Comparator: Expectant Treatment; Expectant PDA management is characterized as 'watchful waiting'. No intervention is initiated with the intention to close a PDA unless defi-nitely needed based of the predefined infant's condition.	Other: Expectant Management; Expectative PDA management is character-ized as 'watchful waiting'. No intervention is initiated with the intention to close a PDA.; Other Names: Conservative management

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PDA re-opening rate	PDA re-opening after echocardiographically documented closure	Day 1 up to 3 month
Closure rate of PDA within a week after the first and second course of pharmacological treatment		Participants will be evaluated at the end of first and second course, at an expected avarage of 10 days of life
The need for surgical ductus closure		Day 1 up to 3 month
Duration of any ventilation assist	The ventilation assist time period	Day 1 up to 3 month
Duration of oxygen supplementation	Days on supplement oxygen	Day 1 up to 3 month
Age of administration of full volume of enteral nutrition		Day 1 up to 3 month
Incidence of oliguria		In the first 14 days of life
Incidence of hypotension		Day 1 up to 3 month
Incidence of BPD		36 weeks PMA
Mortality rate		36 weeks PMA
Incidence of severe intraventricular hemorrhage		28-days since birth
Incidence of necrotizing enterocolitis (Bell stage ≥ IIa)		36 weeks PMA
Incidence of periventricular leukomalacia		36 weeks PMA

Collaborators and Investigators

• Sponsor: Lviv National Medical University
• Investigators: Principal Investigator: Dmytro Dobryanskyy, MD, PhD, L'viv National Medical University

Publications and helpful links

General Publications

• Potsiurko S, Dobryanskyy D, Sekretar L. Patent ductus arteriosus, systemic NT-proBNP concentrations and development of bronchopulmonary dysplasia in very preterm infants: retrospective data analysis from a randomized controlled trial. BMC Pediatr. 2021 Jun 19;21(1):286. doi: 10.1186/s12887-021-02750-9.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2019
• Primary Completion (Actual): July 20, 2021
• Study Completion (Actual): July 20, 2021

Study Registration Dates

• First Submitted: February 16, 2019
• First Submitted That Met QC Criteria: March 1, 2019
• First Posted (Actual): March 4, 2019

Study Record Updates

• Last Update Posted (Actual): April 13, 2022
• Last Update Submitted That Met QC Criteria: April 5, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: PDA; Ibuprofen; Paracetamol; Expectant management
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; 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; Antipyretics; Acetaminophen; Ibuprofen; Cyclooxygenase Inhibitors
• Other Study ID Numbers: 04011994

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No