CANRxPDA: Canadian National PDA Treatment Study

Sponsor

IWK Health Centre (Other)

Overall Status

Recruiting

CT.gov ID

NCT04347720

Collaborator

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 (Other), The Hospital for Sick Children (Other), Health Sciences Centre, Winnipeg, Manitoba (Other), St. Justine's Hospital (Other), Kingston Health Sciences Centre (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 (Other), Horizon Health Network (Other), Sunnybrook Health Sciences Centre (Other), Windsor Regional Hospital (Other), Royal Columbian Hospital (Other), Centre de recherche du Centre hospitalier universitaire de Sherbrooke (Other), London Health Sciences Centre (Other), Canadian Institutes of Health Research (CIHR) (Other)

1,350

Enrollment

Locations

Anticipated Duration (Months)

61.4

Patients Per Site

1.4

Patients Per Site Per Month

Study Details

Study Description

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:

Standard dose ibuprofen [10-5-5 regimen, i.e., 10mg/kg followed by 2 doses of 5mg/kg at 24h intervals]
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]
Intravenous indomethacin [0.1-0.3mg/kg every 12-24h for a total of 3 doses].
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.

Condition or Disease	Intervention/Treatment	Phase
Patent Ductus Arteriosus Extreme Prematurity	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 Design

Study Type:

Observational [Patient Registry]

Anticipated Enrollment :

1350 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

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

Actual Study Start Date :

Jan 1, 2020

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

Sep 1, 2023

Arms and Interventions

Arm	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

Outcome Measures

Primary Outcome Measures

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

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
Necrotizing enterocolitis [through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)]
Stage 2 or greater as per Bell's criteria
Severe intraventricular hemorrhage [through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)]
Grade III-IV according to Papile 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
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
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]
All-cause mortality during hospital stay [through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 12 Weeks

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Foothills Medical Centre	Calgary	Alberta	Canada
2	Royal Alexandra Hospital	Edmonton	Alberta	Canada
3	Royal Columbian Hospital	New Westminster	British Columbia	Canada
4	British Columbia Women's Hospital	Vancouver	British Columbia	Canada
5	Victoria General Hospital	Victoria	British Columbia	Canada
6	Health Sciences Centre	Winnipeg	Manitoba	Canada
7	St. Boniface General Hospital	Winnipeg	Manitoba	Canada
8	The Moncton Hospital	Moncton	New Brunswick	Canada
9	Saint John Regional Hospital	Saint John	New Brunswick	Canada
10	IWK Health Center	Halifax	Nova Scotia	Canada	B3K 6R8
11	Kingston Health Sciences Centre	Kingston	Ontario	Canada
12	London Health Sciences Centre	London	Ontario	Canada
13	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada
14	Hospital for Sick Children	Toronto	Ontario	Canada
15	Mount Sinai Hospital	Toronto	Ontario	Canada
16	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada
17	Windsor Regional Hospital	Windsor	Ontario	Canada
18	CHU Sainte-Justine	Montréal	Quebec	Canada
19	Centre Hospitalier Universitaire de Quebec	Québec City	Quebec	Canada
20	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke	Quebec	Canada
21	Regina General Hospital	Regina	Saskatchewan	Canada
22	Royal University Hospital	Saskatoon	Saskatchewan	Canada

Sponsors and Collaborators

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

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