Canadian National PDA Treatment Study (CANRxPDA)

Relative Effectiveness and Safety of Pharmacotherapeutic Agents for Patent Ductus Arteriosus (PDA) in Preterm Infants: A National Comparative Effectiveness Research (CER) Project

Patent ductus arteriosus (PDA) is the most common cardiovascular problem that develops in preterm infants. Persistent PDA may result in higher rates of death, chronic lung disease (CLD), pulmonary hemorrhage, necrotizing enterocolitis (NEC), acute kidney injury (AKI), intraventricular hemorrhage (IVH) and cerebral palsy. Currently available options to treat a PDA include indomethacin, ibuprofen or acetaminophen followed by surgical or interventional closure of the PDA if medical therapy fails.

Wide variation exists in PDA treatment practices across Canada. A survey conducted through the Canadian Neonatal Network (CNN) in 2019 showed that the most common choice of initial pharmacotherapy is standard dose ibuprofen. In view of the high pharmacotherapy failure rate with standard dose ibuprofen, there is a growing use of higher doses of ibuprofen with increasing postnatal age (with 32% of respondents currently adopting this practice) in spite of the fact that effectiveness and safety of higher ibuprofen doses have not been established in extremely preterm infants [<29 weeks gestational age (GA)]. In view of this large practice variation across Canadian neonatal intensive care units (NICUs), we are planning a comparative effectiveness study of the different primary pharmacotherapeutic agents used to treat the PDA in preterm infants.

Aims Primary: To compare the primary pharmacotherapeutic practices for PDA closure and evaluate their impact on clinical outcomes in extremely preterm infants (<29 weeks GA) Secondary: To understand the relevance of pharmacotherapeutic PDA treatment with respect to clinical outcomes in the real world.

Methods:

Participants: Extremely preterm infants (<29 weeks gestational age) with an echocardiography confirmed PDA who will be treated according to attending team

Interventions:

1. Standard dose ibuprofen [10-5-5 regimen, i.e., 10mg/kg followed by 2 doses of 5mg/kg at 24h intervals]
2. Adjustable dose ibuprofen [10-5-5 regimen if treated within the first week. Higher doses of ibuprofen up to a 20-10-10 regimen if treated after the postnatal age cut-off for lower dose as per the local center policy]
3. Intravenous indomethacin [0.1-0.3mg/kg every 12-24h for a total of 3 doses].
4. Acetaminophen [Oral/intravenous] (15mg/kg every 6h) for 3-7 days

Outcomes:

Primary: Failure of primary pharmacotherapy (Need for further medical and/or surgical/interventional treatment following an initial course of pharmacotherapy).

Secondary: (a) Receipt of 2nd course of pharmacotherapy; (b) Surgical/interventional PDA closure; (c) CLD (d) NEC (stage 2 or greater) (e) Severe IVH (Grade III-IV) (f) Definite sepsis (g) Stage 1 or greater AKI; (h) Post-treatment serum bilirubin; (i) Phototherapy duration; (j) All-cause mortality during hospital stay.

Study Overview

• Status: Completed
• Conditions: Patent Ductus Arteriosus; Extreme Prematurity
• Intervention / Treatment: Drug: Indomethacin; Drug: Ibuprofen; Drug: Acetaminophen

Detailed Description

In this study, we intend to generate real-world evidence (RWE) by analyzing real-world data (RWD) (defined as data generated during routine clinical practice) from a registry-based Comparative Effectiveness Research study.

The Canadian Neonatal Network (CNN) is a well-established patient registry that includes members from 31 hospitals and 17 universities across Canada. The Network maintains a standardized NICU database and provides a unique opportunity for researchers to participate in collaborative projects. We will use the principles of Hypotheses Evaluating Treatment Effectiveness (HETE) research, which are designed to evaluate the presence or absence of a pre-specified effect and/or its magnitude. The network has recent experience in conducting such a study where one CIHR-funded study to evaluate effectiveness of two modes of non-invasive ventilation in preterm infants is already underway in 20 NICUs across Canada.

The CNN's coordinating facility is located within the Maternal-Infant Care (MiCare) Research Center, Lunenfeld-Tanenbaum Research Institute (LTRI) at Mount Sinai Hospital (Toronto). Each participating site has highly trained abstractors who enter data from patient charts into the CNN database. The abstractors will also enter data specific to our project, which will allow us to obtain real-world data at a minimal cost with easy access to investigators for troubleshooting.

Statistical Analysis overview: Since the proposed study is a CER using RWD, we will examine and account for potential confounders at the analyses stage. As recommended for HETE studies using RWD, accuracy of results will be checked by performing complementary sensitivity analyses. The analyses will be conducted in 2 stages: unit-level protocol effectiveness analysis and a secondary drug-dosage effectiveness analysis.

• Study Type: Observational
• Enrollment (Actual): 1663

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Foothills Medical Centre
    • Edmonton, Alberta, Canada
      • Royal Alexandra Hospital
  • British Columbia
    • New Westminster, British Columbia, Canada
      • Royal Columbian Hospital
    • Vancouver, British Columbia, Canada
      • British Columbia Women's Hospital
    • Victoria, British Columbia, Canada
      • Victoria General Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • St. Boniface General Hospital
    • Winnipeg, Manitoba, Canada
      • Health Sciences Centre
  • New Brunswick
    • Moncton, New Brunswick, Canada
      • The Moncton Hospital
    • Saint John, New Brunswick, Canada
      • Saint John Regional Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Center
  • Ontario
    • Kingston, Ontario, Canada
      • Kingston Health Sciences Centre
    • London, Ontario, Canada
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada
      • Hospital for Sick Children
    • Windsor, Ontario, Canada
      • Windsor Regional Hospital
  • Quebec
    • Montréal, Quebec, Canada
      • CHU Sainte-Justine
    • Québec City, Quebec, Canada
      • Centre Hospitalier Universitaire de Quebec
    • Sherbrooke, Quebec, Canada
      • Centre Hospitalier Universitaire de Sherbrooke
  • Saskatchewan
    • Regina, Saskatchewan, Canada
      • Regina General Hospital
    • Saskatoon, Saskatchewan, Canada
      • Royal University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 months (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

All infants born less than 29 weeks of gestation admitted to the participating sites will be included in the study. The population of interest will be those preterm infants <29 weeks gestational age (including outborns) with echocardiography confirmed PDA who will be treated according to attending team. Infants <29 weeks GA with echocardiography-confirmed PDA but never received treatment will be included as the control population. Infants <29 weeks GA who were never diagnosed with PDA will be included as the reference population

Description

Inclusion Criteria:

• Extremely preterm infants (<29 weeks gestational age) with an echocardiography confirmed PDA who will be treated according to attending team

Exclusion Criteria:

• Any infant who received pharmacotherapy for a clinically symptomatic PDA without prior echocardiographic confirmation of the presence of PDA will be excluded from all analyses.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Indomethacin Arm; Intravenous indomethacin at 0.1-0.3 mg/kg IV every 12-24h for a total of 3 doses as choice of initial pharmacotherapy.	Drug: Indomethacin; Intravenous formulation; Other Names: indocid
Standard dose ibuprofen Arm; Standard dose ibuprofen [Oral/intravenous] at 10 mg/kg followed by 2 doses of 5mg/kg at 24 h intervals irrespective of postnatal age as choice of initial pharmacotherapy.	Drug: Ibuprofen; Intravenous and oral formulations; Other Names: Advil; NeoProfen
Adjustable dose ibuprofen Arm; Adjustable dose ibuprofen [Oral/intravenous] as choice of initial pharmacotherapy. The dose of ibuprofen will be 10 mg/kg followed by 2 doses of 5 mg/kg at 24 h intervals if treated within the first 7 days after birth. Higher doses of ibuprofen up to 20 mg/kg followed by 2 doses of 10 mg/kg at 24 h intervals if treated after the postnatal age cut-off for lower dose as per the local center policy	Drug: Ibuprofen; Intravenous and oral formulations; Other Names: Advil; NeoProfen
Acetaminophen Arm; Acetaminophen [Oral/intravenous] at 15mg/kg every 6h for 3-7 days as choice of initial pharmacotherapy.	Drug: Acetaminophen; Intravenous and oral formulations; Other Names: paracetamol
Control group; Infants <29 weeks GA with echocardiography-confirmed PDA but never received any pharmacotherapy
Reference group; Infants <29 weeks GA who were never diagnosed with PDA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Failure of primary pharmacotherapy	Receipt of further medical and/or surgical/interventional treatment following an initial course of pharmacotherapy	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
Chronic lung disease	Oxygen or respiratory support requirement at 36 weeks' postmenstrual age or at discharge	birth through 36 weeks post menstrual age
Severe intraventricular hemorrhage	Grade III-IV according to Papile Criteria	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)
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)
Receipt of 2nd course of pharmacotherapy		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Acute Kidney Injury	Stage 1 or greater according to the Neonatal AKI KDIGO classification	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Post-treatment serum bilirubin		within 7 days of initiation of pharmacotherapy
Maximum serum AST and ALT (u/L) during treatment or within 1 week of treatment completion		within 7 days of completion of pharmacotherapy

Collaborators and Investigators

• Sponsor: IWK Health Centre
• Collaborators: The Hospital for Sick Children; Sunnybrook Health Sciences Centre; Canadian Institutes of Health Research (CIHR); Health Sciences Centre, Winnipeg, Manitoba; CHU de Quebec-Universite Laval; Centre de recherche du Centre hospitalier universitaire de Sherbrooke; Queen's University; London Health Sciences Centre; Children's Hospital of Eastern Ontario; MOUNT SINAI HOSPITAL; St. Justine's Hospital; Provincial Health Services Authority; Horizon Health Network; Royal University Hospital Foundation; St. Boniface Hospital; Royal Alexandra Hospital; Foothills Medical Centre; Regina General Hospital; Victoria General Hospital; The Moncton Hospital; Windsor Regional Hospital; Royal Columbian Hospital
• Investigators: Principal Investigator: Souvik Mitra, MD, MSc, IWK Health Center, Halifax, Canada; Principal Investigator: Amish Jain, MBBS, PhD, Mount Sinai Hospital, Canada; Principal Investigator: Prakeshkumar Shah, MD, FRCPC, Mount Sinai Hospital, Canada

Publications and helpful links

General Publications

• Mitra S, Jain A, Ting JY, Ben Fadel N, Drolet C, Abou Mehrem A, Soraisham A, Jasani B, Louis D, Lapointe A, Dorling J, Khurshid F, Hyderi A, Kumaran K, Bodani J, Weisz D, Alvaro R, Adie M, Stavel M, Morin A, Bhattacharya S, Kanungo J, Canning R, Ye XY, Hatfield T, Gardner CE, Shah P. Relative effectiveness and safety of pharmacotherapeutic agents for patent ductus arteriosus (PDA) in preterm infants: a protocol for a multicentre comparative effectiveness study (CANRxPDA). BMJ Open. 2021 May 5;11(5):e050682. doi: 10.1136/bmjopen-2021-050682.

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 1, 2020
• Primary Completion (Actual): July 31, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: April 12, 2020
• First Submitted That Met QC Criteria: April 12, 2020
• First Posted (Actual): April 15, 2020

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: acetaminophen; ibuprofen; indomethacin
• 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; Cyclooxygenase Inhibitors; Antipyretics; Reproductive Control Agents; Gout Suppressants; Tocolytic Agents; Acetaminophen; Ibuprofen; Indomethacin
• Other Study ID Numbers: 1025627

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