Canadian National PDA Treatment Study

Patent Ductus Arteriosus Clinical Trial

— CANRxPDA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04347720
• Other study ID #: 1025627
• Status: Recruiting
• Start date: January 1, 2020
• Est. completion date: September 1, 2023

Study information

• Verified date: April 2023
• Source: IWK Health Centre
• Contact: Souvik Mitra, MD, MSc
• Phone: +1-902-470-6490
• Email: souvik.mitra[@]iwk.nshealth.ca
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 1350
• Est. completion date: September 1, 2023
• Est. primary completion date: August 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 12 Weeks

Eligibility

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.

Related Conditions & MeSH terms

• Ductus Arteriosus, Patent
• Extreme Prematurity
• Patent Ductus Arteriosus

Intervention

Drug:
• Indomethacin
Intravenous formulation
• Ibuprofen
Intravenous and oral formulations
• Acetaminophen
Intravenous and oral formulations

Locations

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

Sponsors (23)

Lead Sponsor

Collaborator

IWK Health Centre

Canadian Institutes of Health Research (CIHR), Centre de recherche du Centre hospitalier universitaire de Sherbrooke, Children's Hospital of Eastern Ontario, CHU de Quebec-Universite Laval, Foothills Medical Centre, Health Sciences Centre, Winnipeg, Manitoba, Horizon Health Network, London Health Sciences Centre, MOUNT SINAI HOSPITAL, Provincial Health Services Authority, Queen's University, Regina General Hospital, Royal Alexandra Hospital, Royal Columbian Hospital, Royal University Hospital Foundation, St. Boniface Hospital, St. Justine's Hospital, Sunnybrook Health Sciences Centre, The Hospital for Sick Children, The Moncton Hospital, Victoria General Hospital, Windsor Regional Hospital

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Receipt of 2nd course of pharmacotherapy		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Secondary	Surgical/interventional PDA closure		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Secondary	Chronic lung disease	Oxygen or respiratory support requirement at 36 weeks' postmenstrual age or at discharge	birth through 36 weeks post menstrual age
Secondary	Necrotizing enterocolitis	Stage 2 or greater as per Bell's criteria	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Secondary	Severe intraventricular hemorrhage	Grade III-IV according to Papile Criteria	through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Secondary	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)
Secondary	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)
Secondary	Post-treatment serum bilirubin		within 7 days of initiation of pharmacotherapy
Secondary	Maximum serum AST and ALT (u/L) during treatment or within 1 week of treatment completion		within 7 days of completion of pharmacotherapy
Secondary	All-cause mortality during hospital stay		through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)

External Links

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