Canadian National PDA Treatment Study

Study Overview
=================
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.

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.

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

Conditions
-----------------
Patent Ductus Arteriosus, Extreme Prematurity

Intervention / Treatment
-----------------
* Drug: Indomethacin
* Drug: Ibuprofen
* Drug: Acetaminophen


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Maximum Age: 12 Weeks

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Indomethacin Arm<br>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<br>* Intravenous formulation<br>* Other names: indocid;|
| Standard dose ibuprofen Arm<br>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<br>* Intravenous and oral formulations<br>* Other names: NeoProfen;|
| Adjustable dose ibuprofen Arm<br>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<br>* Intravenous and oral formulations<br>* Other names: NeoProfen;|
| Acetaminophen Arm<br>Acetaminophen [Oral/intravenous] at 15mg/kg every 6h for 3-7 days as choice of initial pharmacotherapy. | Drug: Acetaminophen<br>* Intravenous and oral formulations<br>* Other names: paracetamol;|
| Control group<br>Infants <29 weeks GA with echocardiography-confirmed PDA but never received any pharmacotherapy | |
| Reference group<br>Infants <29 weeks GA who were never diagnosed with PDA | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Oxygen or respiratory support requirement at 36 weeks' postmenstrual age or at discharge | birth through 36 weeks post menstrual age | 
| Necrotizing enterocolitis | Stage 2 or greater as per Bell's criteria | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| Severe intraventricular hemorrhage | Grade III-IV according to Papile Criteria | through hospital discharge (approximately 20 weeks postnatal age unless death occurs first) | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
indomethacin, ibuprofen, acetaminophen