Canadian National PDA Treatment Study
- Conditions
- Patent Ductus ArteriosusExtreme Prematurity
- Interventions
- Registration Number
- NCT04347720
- Lead Sponsor
- IWK Health Centre
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1663
- Extremely preterm infants (<29 weeks gestational age) with an echocardiography confirmed PDA who will be treated according to attending team
- 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 & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Indomethacin Arm Indomethacin Intravenous indomethacin at 0.1-0.3 mg/kg IV every 12-24h for a total of 3 doses as choice of initial pharmacotherapy. Standard dose ibuprofen Arm Ibuprofen 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. Acetaminophen Arm Acetaminophen Acetaminophen \[Oral/intravenous\] at 15mg/kg every 6h for 3-7 days as choice of initial pharmacotherapy. Adjustable dose ibuprofen Arm Ibuprofen 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
- Primary Outcome Measures
Name Time Method Failure of primary pharmacotherapy through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) Receipt of further medical and/or surgical/interventional treatment following an initial course of pharmacotherapy
- Secondary Outcome Measures
Name Time Method Necrotizing enterocolitis through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) Stage 2 or greater as per Bell's criteria
Definite sepsis through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) Clinical symptoms and signs of sepsis and a positive bacterial culture in a specimen obtained from normally sterile fluids or tissue obtained at postmortem
Post-treatment serum bilirubin within 7 days of initiation of pharmacotherapy Receipt of 2nd course of pharmacotherapy 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 birth through 36 weeks post menstrual age Oxygen or respiratory support requirement at 36 weeks' postmenstrual age or at discharge
Severe intraventricular hemorrhage through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) Grade III-IV according to Papile Criteria
Acute Kidney Injury through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) Stage 1 or greater according to the Neonatal AKI KDIGO classification
Maximum serum AST and ALT (u/L) during treatment or within 1 week of treatment completion within 7 days of completion of pharmacotherapy All-cause mortality during hospital stay through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Trial Locations
- Locations (22)
Royal Alexandra Hospital
🇨🇦Edmonton, Alberta, Canada
Regina General Hospital
🇨🇦Regina, Saskatchewan, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Children's Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
Foothills Medical Centre
🇨🇦Calgary, Alberta, Canada
Saint John Regional Hospital
🇨🇦Saint John, New Brunswick, Canada
Windsor Regional Hospital
🇨🇦Windsor, Ontario, Canada
IWK Health Center
🇨🇦Halifax, Nova Scotia, Canada
Health Sciences Centre
🇨🇦Winnipeg, Manitoba, Canada
The Moncton Hospital
🇨🇦Moncton, New Brunswick, Canada
Royal Columbian Hospital
🇨🇦New Westminster, British Columbia, Canada
Royal University Hospital
🇨🇦Saskatoon, Saskatchewan, Canada
Victoria General Hospital
🇨🇦Victoria, British Columbia, Canada
St. Boniface General Hospital
🇨🇦Winnipeg, Manitoba, Canada
London Health Sciences Centre
🇨🇦London, Ontario, Canada
Kingston Health Sciences Centre
🇨🇦Kingston, Ontario, Canada
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Mount Sinai Hospital
🇨🇦Toronto, Ontario, Canada
CHU Sainte-Justine
🇨🇦Montréal, Quebec, Canada
Centre Hospitalier Universitaire de Quebec
🇨🇦Québec City, Quebec, Canada
Centre Hospitalier Universitaire de Sherbrooke
🇨🇦Sherbrooke, Quebec, Canada
British Columbia Women's Hospital
🇨🇦Vancouver, British Columbia, Canada