Clinical trial NCT04347720: Canadian National PDA Treatment Study
Official title: Relative Effectiveness and Safety of Pharmacotherapeutic Agents for Patent Ductus Arteriosus (PDA) in Preterm Infants: A National Comparative Effectiveness Research (CER) Project
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Patent Ductus Arteriosus
Extreme Prematurity
Keywords: indomethacin
ibuprofen
acetaminophen
Lead sponsor: IWK Health Centre
Sponsor class: OTHER
Collaborators: name: Provincial Health Services Authority
name: Children's Hospital of Eastern Ontario
name: CHU de Quebec-Universite Laval
name: Foothills Medical Centre
name: Victoria General Hospital
name: The Hospital for Sick Children
name: Health Sciences Centre, Winnipeg, Manitoba
name: St. Justine's Hospital
name: Queen's University
name: MOUNT SINAI HOSPITAL
name: Royal Alexandra Hospital
name: Regina General Hospital
name: Royal University Hospital Foundation
name: St. Boniface Hospital
name: The Moncton Hospital
name: Horizon Health Network
name: Sunnybrook Health Sciences Centre
name: Windsor Regional Hospital
name: Royal Columbian Hospital Foundation
name: Centre de recherche du Centre hospitalier universitaire de Sherbrooke
name: London Health Sciences Centre
name: Canadian Institutes of Health Research (CIHR)
First posted: 2020-04-15
Enrollment: 1663
Sex: ALL
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Failure of primary pharmacotherapy
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Secondary outcomes:
measure: Receipt of 2nd course of pharmacotherapy
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Surgical/interventional PDA closure
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Chronic lung disease
timeFrame: birth through 36 weeks post menstrual age
measure: Necrotizing enterocolitis
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Severe intraventricular hemorrhage
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Definite sepsis
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Acute Kidney Injury
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
measure: Post-treatment serum bilirubin
timeFrame: within 7 days of initiation of pharmacotherapy
measure: Maximum serum AST and ALT (u/L) during treatment or within 1 week of treatment completion
timeFrame: within 7 days of completion of pharmacotherapy
measure: All-cause mortality during hospital stay
timeFrame: through hospital discharge (approximately 20 weeks postnatal age unless death occurs first)
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: New Westminster
country: Canada
facility: Royal Columbian Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: British Columbia Women's Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Victoria General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: Health Sciences Centre
state: Manitoba
city: Winnipeg
country: Canada
facility: St. Boniface General Hospital
state: Manitoba
city: Moncton
country: Canada
facility: The Moncton Hospital
state: New Brunswick
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Halifax
country: Canada
facility: IWK Health Center
state: Nova Scotia
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Hospital
state: Ontario
city: Montréal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Québec City
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Regina General Hospital
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
Study officials:
affiliation: IWK Health Center, Halifax, Canada
name: Souvik Mitra, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Mount Sinai Hospital, Canada
name: Amish Jain, MBBS, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mount Sinai Hospital, Canada
name: Prakeshkumar Shah, MD, FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.