Selective Early Medical Treatment of Patent Ductus Arteriosus in Extremely Low Gestational Age Infants: A Pilot RCT (SMART-PDA)

Selective Early Medical Treatment of the Patent Ductus Arteriosus in Extremely Low Gestational Age Infants: A Pilot Randomized Controlled Trial

Background: Among preterm infants, those born at a gestational age less than 26 weeks are considered the most vulnerable with a high risk of short- and long-term health problems that include chronic lung disease, brain bleeds, gut injury, kidney failure and death. Patent ductus arteriosus (PDA) is the most common heart condition with almost 70% preterm infants in this gestational age group being diagnosed with a PDA. Though many PDAs spontaneously resolve on their own, research suggests that if the PDA persists, it may contribute to a number of these short- and long-term health problems. Non-steroidal anti-inflammatory medications such as ibuprofen are commonly used to treat a PDA. Such drugs can also have harmful effects on the gut and kidneys of extremely preterm infants. Therefore, we are unsure if early treatment of a symptomatic PDA in this age group is at all beneficial. Given the wide variation in PDA treatment approaches in this age group, a randomized trial design, where extremely preterm infants with a symptomatic PDA are randomly assigned to early treatment or no early treatment, is essential to address this question.

Purpose of the study: The overall purpose of this pilot study is to assess the feasibility of conducting a large study to explore the following research question: In preterm infants born <26 weeks' gestation, is a strategy of selective early medical treatment of a symptomatic PDA better than no treatment at all in the first week of life?

The main feasibility objectives of this study are:

1. To assess how many eligible infants can be enrolled in the study
2. To assess how many enrolled infants properly complete the study protocol

Importance: To our knowledge this will be the first study on PDA management in preterm infants that specifically aims to enroll preterm infants born at <26 weeks of gestational age who are at the highest risk for PDA-related problems but have been mostly under-represented in previous PDA studies.

Study Overview

• Status: Recruiting
• Conditions: Patent Ductus Arteriosus After Premature Birth
• Intervention / Treatment: Drug: Ibuprofen

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Souvik Mitra, MD, MSc; Phone Number: +1-902-470-6490; Email: souvik.mitra@iwk.nshealth.ca
• Study Contact Backup: Name: Amish Jain, MBBS, PhD; Email: amish.jain@sinaihealth.ca

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • Recruiting
      • Stollery Children's Hospital
      • Contact: Abbas Hyderi
      • Sub-Investigator: Joseph Ting
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Recruiting
      • British Columbia Women's Hospital
      • Contact: Michael Castaldo
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • Recruiting
      • IWK Health Center
      • Contact: Souvik Mitra
      • Sub-Investigator: Walid El-Naggar
  • Ontario
    • Toronto, Ontario, Canada
      • Withdrawn
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada
      • Withdrawn
      • Sunnybrook Health Sciences Centre
  • Quebec
    • Québec City, Quebec, Canada
      • Recruiting
      • Centre Hospitalier Universitaire de Quebec
      • Contact: Audrey Hébert
• United States
  • California
    • Orange, California, United States, 92868
      • Recruiting
      • Children's Hospital of Orange County
      • Contact: John Cleary
    • San Diego, California, United States, 92123
      • Terminated
      • Sharp Mary Birch Hospital for Women & Newborns
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73117
      • Recruiting
      • OU College of Medicine, University of Oklahoma
      • Contact: Marjorie Makoni, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 days (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Preterm infants less than 26 completed weeks (i.e., up to and including 25 weeks and 6 days) of gestation

Exclusion Criteria:

• no PDA on initial screening echocardiography
• congenital heart disease (excluding patent foramen ovale, atrial septal defect or ventricular septal defect with a defect size less than 2mm)
• other major congenital anomaly
• decision to withhold/withdraw care

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Selective early medical treatment (SMART) strategy; Infants who are randomized to experimental group will follow the SMART treatment protocol, which includes echocardiographic screening every 72 hours to categorize PDA disease severity by combining clinical and echocardiographic features. At any evaluation if patients are found to have a "severe PDA" on echocardiography, irrespective of clinical symptoms, or a "moderate PDA" on echocardiography with at least moderate clinical illness, they will receive pharmacotherapy aimed at PDA closure (The PDA severity has been divided into mild, moderate or severe based on pre-defined clinical and echocardiographic criteria).	Drug: Ibuprofen; Pharmacotherapy, when indicated (ie, for "severe PDA" on echocardiography, irrespective of clinical symptoms, or a "moderate PDA" on echocardiography with at least moderate clinical illness), will be provided in the form of ibuprofen as first line agent at a standard dosing of 10 mg/kg followed by 2 doses of 5mg/kg every 24 h. The route of administration may be intravenous or enteral, as determined by the treating team. For treated infants, follow-up echocardiography will be conducted at the end of the 3-day course and second course of treatment will be initiated if they still fulfill study treatment criteria as mentioned above. If any treatment-eligible infant has a contraindication to ibuprofen, use of acetaminophen will be permitted as an alternative agent.
No Intervention: Early conservative management strategy; Infants randomized to this arm will not undergo any further echocardiographic assessment or pharmacological treatment of the PDA regardless of the clinical signs. If the infant gets an echocardiographic assessment for a reason different than PDA assessment (such as hypotension or oxygenation failure) and a PDA is incidentally noted that fits the treatment criteria, the infant will not be initiated on pharmacotherapy. After 7 days of age, decision on PDA assessment and treatment will be at the discretion of the treating physician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of eligible infants recruited during the study period	7 days postnatal age
Proportion of randomized infants with no reported protocol deviations	7 days postnatal age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of infants in control group meeting pre-defined safety criteria		7 days postnatal age
Reasons for non-recruitment	qualitative description of reasons for non-recruitment of eligible infants	7 days postnatal age
Reasons for non-adherence to protocol	qualitative description of reasons for non-adherence to protocol in randomized infants	7 days postnatal age
Completeness of data collection for clinical outcomes	Proportion of recruited infants with complete clinical outcome data	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
All-cause mortality during hospital stay		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Surgical/interventional PDA closure		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Receipt of any PDA pharmacotherapy		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Receipt of open-label rescue medical treatment in the control group		7 days postnatal age
Chronic lung disease	Oxygen or respiratory support requirement at 36 weeks' postmenstrual age or at discharge	birth through 36 weeks post menstrual age
Postnatal corticosteroid use		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Pulmonary hemorrhage	blood-stained respiratory secretions with a significant increase in respiratory requirements (MAP>12 and/or FiO2>60%)	7 days postnatal age
Duration of invasive mechanical ventilation	Number of days on mechanical ventilation with an endotracheal tube	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Intraventricular hemorrhage	Grade I-IV according to Papile Criteria	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Severe intraventricular hemorrhage	Grade III-IV according to Papile Criteria	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Periventricular leukomalacia		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Necrotizing enterocolitis	Stage 2 or greater as per Bell's criteria	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Gastrointestinal bleeding		within seven days of the first dose of pharmacotherapy
Gastrointestinal perforation		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Severe retinopathy of prematurity	stage 3 or greater	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Definite sepsis	Clinical symptoms and signs of sepsis and a positive bacterial culture in a specimen obtained from normally sterile fluids or tissue obtained at postmortem	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Oliguria	urine output less than 1 mL/kg/hour	7 days postnatal age
Duration of hospitalization (days)		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)

Collaborators and Investigators

• Sponsor: IWK Health Centre
• Collaborators: Sunnybrook Health Sciences Centre; Canadian Institutes of Health Research (CIHR); University of Oklahoma; CHU de Quebec-Universite Laval; University of Alberta; Mount Sinai Hospital, Canada; Dalhousie Medical Research Foundation; BC Children's Hospital Research Institute; Sharp Mary Birch Hospital for Women & Newborns; Children's Hospital of Orange County, OC, California, United States
• Investigators: Principal Investigator: Souvik Mitra, MD, MSc, Dalhousie University & IWK Health

Publications and helpful links

Helpful Links

• Project funding information on the Canadian Institutes of Health Research (CIHR) Funding Decision Database

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2022
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): September 30, 2024

Study Registration Dates

• First Submitted: August 12, 2021
• First Submitted That Met QC Criteria: August 12, 2021
• First Posted (Actual): August 18, 2021

Study Record Updates

• Last Update Posted (Actual): June 21, 2024
• Last Update Submitted That Met QC Criteria: June 18, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: randomized controlled trial; extremely preterm infant; early medical treatment
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Heart Defects, Congenital; Cardiovascular Abnormalities; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; 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: 459750

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data on clinical outcomes collected during the trial will be shared after deidentification.
• IPD Sharing Time Frame: As soon as possible, wherever legally and ethically possible. In addition, data from the trial will be made available upon reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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