Study Results
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Basic Information
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COMPLETED
1663 participants
OBSERVATIONAL
2020-01-01
2023-12-31
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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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.
Indomethacin
Intravenous formulation
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.
Ibuprofen
Intravenous and oral formulations
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
Ibuprofen
Intravenous and oral formulations
Acetaminophen Arm
Acetaminophen \[Oral/intravenous\] at 15mg/kg every 6h for 3-7 days as choice of initial pharmacotherapy.
Acetaminophen
Intravenous and oral formulations
Control group
Infants \<29 weeks GA with echocardiography-confirmed PDA but never received any pharmacotherapy
No interventions assigned to this group
Reference group
Infants \<29 weeks GA who were never diagnosed with PDA
No interventions assigned to this group
Interventions
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Indomethacin
Intravenous formulation
Ibuprofen
Intravenous and oral formulations
Acetaminophen
Intravenous and oral formulations
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
Exclusion Criteria
12 Weeks
ALL
No
Sponsors
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Provincial Health Services Authority
OTHER
Children's Hospital of Eastern Ontario
OTHER
CHU de Quebec-Universite Laval
OTHER
Foothills Medical Centre
OTHER
Victoria General Hospital
UNKNOWN
The Hospital for Sick Children
OTHER
Health Sciences Centre, Winnipeg, Manitoba
OTHER
St. Justine's Hospital
OTHER
Queen's University
OTHER
MOUNT SINAI HOSPITAL
OTHER
Royal Alexandra Hospital
OTHER
Regina General Hospital
OTHER
Royal University Hospital Foundation
OTHER
St. Boniface Hospital
OTHER
The Moncton Hospital
UNKNOWN
Horizon Health Network
OTHER
Sunnybrook Health Sciences Centre
OTHER
Windsor Regional Hospital
OTHER
Royal Columbian Hospital Foundation
OTHER
Centre de recherche du Centre hospitalier universitaire de Sherbrooke
OTHER
London Health Sciences Centre
OTHER
Canadian Institutes of Health Research (CIHR)
OTHER_GOV
IWK Health Centre
OTHER
Responsible Party
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Dr. Souvik Mitra, MD MSc FRCPC
Assistant Professor
Principal Investigators
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Souvik Mitra, MD, MSc
Role: PRINCIPAL_INVESTIGATOR
IWK Health Center, Halifax, Canada
Amish Jain, MBBS, PhD
Role: PRINCIPAL_INVESTIGATOR
Mount Sinai Hospital, Canada
Prakeshkumar Shah, MD, FRCPC
Role: PRINCIPAL_INVESTIGATOR
Mount Sinai Hospital, Canada
Locations
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Foothills Medical Centre
Calgary, Alberta, Canada
Royal Alexandra Hospital
Edmonton, Alberta, Canada
Royal Columbian Hospital
New Westminster, British Columbia, Canada
British Columbia Women's Hospital
Vancouver, British Columbia, Canada
Victoria General Hospital
Victoria, British Columbia, Canada
Health Sciences Centre
Winnipeg, Manitoba, Canada
St. Boniface General Hospital
Winnipeg, Manitoba, Canada
The Moncton Hospital
Moncton, New Brunswick, Canada
Saint John Regional Hospital
Saint John, New Brunswick, Canada
IWK Health Center
Halifax, Nova Scotia, Canada
Kingston Health Sciences Centre
Kingston, Ontario, Canada
London Health Sciences Centre
London, Ontario, Canada
Children's Hospital of Eastern Ontario
Ottawa, Ontario, Canada
Hospital for Sick Children
Toronto, Ontario, Canada
Mount Sinai Hospital
Toronto, Ontario, Canada
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada
Windsor Regional Hospital
Windsor, Ontario, Canada
CHU Sainte-Justine
Montreal, Quebec, Canada
Centre Hospitalier Universitaire de Quebec
Québec, Quebec, Canada
Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke, Quebec, Canada
Regina General Hospital
Regina, Saskatchewan, Canada
Royal University Hospital
Saskatoon, Saskatchewan, Canada
Countries
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References
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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.
Related Links
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Project funding information on the Canadian Institutes of Health Research (CIHR) Funding Decision Database
Other Identifiers
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1025627
Identifier Type: -
Identifier Source: org_study_id
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