Canadian National PDA Treatment Study

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Patent ductus arteriosus
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Safety and Effectiveness Study With a New PDA Occluder for Closure of Patent Ductus Arteriosus

Brief Title

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

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.

Study Type

Observational [Patient Registry]

Primary Outcome

Failure of primary pharmacotherapy

Secondary Outcome

 Receipt of 2nd course of pharmacotherapy

Condition

Patent Ductus Arteriosus

Intervention

Indomethacin

Study Arms / Comparison Groups

 Indomethacin Arm
Description:  Intravenous indomethacin at 0.1-0.3 mg/kg IV every 12-24h for a total of 3 doses as choice of initial pharmacotherapy.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status

Drug

Estimated Enrollment

1350

Start Date

January 1, 2020

Completion Date

September 2023

Primary Completion Date

April 2023

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.

Gender

All

Ages

N/A - 12 Weeks

Accepts Healthy Volunteers

No

Contacts

Souvik Mitra, MD, MSc, +1-902-470-6490, [email protected]

Location Countries

Canada

Location Countries

Canada

Administrative Informations

NCT ID

NCT04347720

Organization ID

1025627

Responsible Party

Principal Investigator

Study Sponsor

IWK Health Centre

Collaborators

 Provincial Health Services Authority

Study Sponsor

Souvik Mitra, MD, MSc, Principal Investigator, IWK Health Center, Halifax, Canada

Verification Date

December 2020