Relative Effectiveness and Safety of Pharmacotherapeutic Agents for Patent Ductus Arteriosus (PDA) in Preterm Infants: A National Comparative Effectiveness Research (CER) Project
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 1,663
- 试验地点
- 22
- 主要终点
- Failure of primary pharmacotherapy
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- — 至 12 Weeks（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Extremely preterm infants (<29 weeks gestational age) with an echocardiography confirmed PDA who will be treated according to attending team
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Indomethacin (Drug)
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.
干预措施: Ibuprofen (Drug)
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
干预措施: Ibuprofen (Drug)
Acetaminophen Arm
Acetaminophen [Oral/intravenous] at 15mg/kg every 6h for 3-7 days as choice of initial pharmacotherapy.
干预措施: Acetaminophen (Drug)
结局指标
主要结局
Failure of primary pharmacotherapy
时间窗: 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
次要结局
- Definite sepsis(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Post-treatment serum bilirubin(within 7 days of initiation of pharmacotherapy)
- Necrotizing enterocolitis(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- 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)
- Severe intraventricular hemorrhage(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- Acute Kidney Injury(through hospital discharge (approximately 20 weeks postnatal age unless death occurs first))
- 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))
研究者
Dr. Souvik Mitra, MD MSc FRCPC
Assistant Professor
IWK Health Centre