Canadian National PDA Treatment Study

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.

Conditions

• Patent Ductus Arteriosus
• Extreme Prematurity

Interventions

DRUG

Indomethacin

Intravenous formulation

DRUG

Ibuprofen

Intravenous and oral formulations

DRUG

Acetaminophen

Intravenous and oral formulations

Sponsors & Collaborators

• Provincial Health Services Authority

  collaborator OTHER

• Children's Hospital of Eastern Ontario

  collaborator OTHER

• CHU de Quebec-Universite Laval

  collaborator OTHER

• Foothills Medical Centre

  collaborator OTHER

• Victoria General Hospital

  collaborator UNKNOWN

• The Hospital for Sick Children

  collaborator OTHER

• Health Sciences Centre, Winnipeg, Manitoba

  collaborator OTHER

• St. Justine's Hospital

  collaborator OTHER

• Queen's University

  collaborator OTHER

• MOUNT SINAI HOSPITAL

  collaborator OTHER

• Royal Alexandra Hospital

  collaborator OTHER

• Regina General Hospital

  collaborator OTHER

• Royal University Hospital Foundation

  collaborator OTHER

• St. Boniface Hospital

  collaborator OTHER

• The Moncton Hospital

  collaborator UNKNOWN

• Horizon Health Network

  collaborator OTHER

• Sunnybrook Health Sciences Centre

  collaborator OTHER

• Windsor Regional Hospital

  collaborator OTHER

• Royal Columbian Hospital Foundation

  collaborator OTHER

• Centre de recherche du Centre hospitalier universitaire de Sherbrooke

  collaborator OTHER

• London Health Sciences Centre

  collaborator OTHER

• Canadian Institutes of Health Research (CIHR)

  collaborator OTHER_GOV

• IWK Health Centre

  lead OTHER

Principal Investigators

• Souvik Mitra, MD, MSc · IWK Health Center, Halifax, Canada

• Amish Jain, MBBS, PhD · Mount Sinai Hospital, Canada

• Prakeshkumar Shah, MD, FRCPC · Mount Sinai Hospital, Canada

Eligibility

Max Age

12 Weeks

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-01-01

Primary Completion

2023-07-31

Completion

2023-12-31

FDA Drug

Yes

Countries

• Canada

Study Locations