Pragmatic Research on Diuretic Management in Early BPD (PRIMED) Pilot

早期 BPD 利尿管理的实用研究 (PRIMED) 试点

• 批准号: 10590825
• 负责人: Anna Maria Hibbs
• 金额: $ 28.94万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590825
• 关键词: Address; Adrenal Cortex Hormones; Affect; Age; Alveolar; Attitude; Belief; Birth Weight; Bronchopulmonary Dysplasia; Childhood; Chlorides; Chronic; Clinical; Clinical Trials; Data; Diuretics; Dose; Dropout; Edema; Effectiveness; Electrolytes; Eligibility Determination; Extremely Low Birth Weight Infant; Functional disorder; Furosemide; Goals; Heterogeneity; Incidence; Infant; Kidney; Liquid substance; Lung; Lung Compliance; Lung diseases; Mechanics; Meta-Analysis; National Heart, Lung, and Blood Institute; Nephrocalcinosis; Osteopenia; Outcome; Oxygen; Parents; Participant; Patients; Phase; Placebo Control; Placebos; Pregnancy; Premature Infant; Provider; Randomized; Randomized, Controlled Trials; Research; Resources; Running; Safety; Sample Size; Series; Sodium; Steroids; Strategic vision; Therapeutic; absorption; adverse outcome; antenatal; clinical practice; clinically relevant; cost; design; evidence base; improved; individual patient; infant outcome; innovation; interstitial; ototoxicity; participant enrollment; premature; respiratory; responders and non-responders; response; side effect; surfactant; symptom management; symptomatic improvement; treatment effect; trial design; willingness

PROJECT SUMMARY/ABSTRACT Bronchopulmonary dysplasia (BPD) is the most frequent adverse outcome among infants born at <30 weeks gestation and is associated with adverse respiratory and neurodevelopmental outcomes. Early BPD includes a component of alveolar and interstitial edema resulting in reduced lung compliance. Some evidence suggests that the use of loop diuretics, such as furosemide, in preterm infants > 3 weeks of age improves pulmonary mechanics and oxygenation after 1 week of treatment; however, the evidence is weak because most studies were not conducted in the current treatment era characterized by widespread surfactant and antenatal corticosteroid use and data focuses mainly on short-term outcomes. Furthermore, diuretics have a range of side effects including electrolyte abnormalities, osteopenia, potential ototoxicity, and nephrocalcinosis. Despite weak evidence for their effectiveness and concerns over safety, diuretics are commonly used. There is a need to strengthen the evidence-base regarding diuretic use in BPD with data that answers the current, relevant clinical questions—whether an individual patient in the current treatment era will derive short- term benefits from the treatment and whether the treatment is safe and effective in the long-term. We designed a clinical trial that addresses prevailing clinical attitudes that some infants clinically benefit or are “responders” by including a run-in period that examines individual patient short-term response using an innovative N-of-1 trial design while also answering questions about the longer-term efficacy and safety of chronic diuretic use by following the run-in N-of-1 trial with a placebo-controlled, parallel group randomized controlled trial (RCT) of chronic diuretics among responders. The objective of this R34 application is to obtain necessary and sufficient information to enable final decisions about the approach of the larger clinical trial through the following specific aims: Aim 1: Estimate the number of responder infants available to enter the parallel group RCT phase of the trial after the N-of-1 trial run-in period and Aim 2: Evaluate provider and parent willingness to randomize responders to assess the potential dropout rate between run-in and randomization. Accomplishing these aims is particularly important because the use of a formal N-of-1 trial design as a run-in to a parallel group RCT is a unique and cutting-edge approach. Upon completion of these aims, this pilot will provide a detailed understanding of the extent to which participants are able to complete the N-of-1 trial and it will supply data on the percent of patients identified as “responders.” This will enable a more accurate assessment of the available sample size entering the parallel group RCT phase of the trial. The pilot will also provide the data necessary to determine the expected dropout rate between the run-in and parallel group RCT phases due to reluctance to randomize a “responder” to furosemide or placebo. Together this information will enable informed decisions about the larger trial sample size and the design of the N-of-1 run-in phase, and it will be of value for others planning studies of diuretics and BPD management strategies.

项目概要/摘要 支气管肺发育不良 (BPD) 是 30 周以下出生婴儿中最常见的不良后果 妊娠并与不良的呼吸和神经发育结果相关。早期的 BPD 包括 肺泡和间质水肿的组成部分，导致肺顺应性降低。一些证据表明 对于 3 周以上的早产儿，使用袢利尿剂（例如呋塞米）可改善肺功能 治疗1周后力学和氧合；然而，证据很薄弱，因为大多数研究 没有在当前以广泛的表面活性剂和产前治疗为特征的时代进行 皮质类固醇的使用和数据主要关注短期结果。此外，利尿剂具有一系列 副作用包括电解质异常、骨质减少、潜在的耳毒性和肾钙质沉着症。尽管 利尿剂的有效性证据薄弱，并且对安全性存在担忧，因此常用利尿剂。有需要 通过回答当前问题的数据来加强有关 BPD 中利尿剂使用的证据基础 相关的临床问题——当前治疗时代的个体患者是否会出现短期症状 治疗的短期获益以及治疗的长期安全性和有效性。我们 设计了一项临床试验，解决一些婴儿在临床上受益或正在受益的普遍临床态度 “反应者”，包括一个磨合期，使用 创新的 N-of-1 试验设计，同时还回答有关长期疗效和安全性的问题 通过遵循安慰剂对照、平行组随机的磨合 N-of-1 试验来长期使用利尿剂 在应答者中进行慢性利尿剂对照试验（RCT）。此 R34 应用程序的目标是获得 必要且充分的信息，以便能够就更大规模的临床试验的方法做出最终决定 通过以下具体目标： 目标 1：估计可进入响应婴儿的数量 N-of1 试验磨合期后试验的平行组 RCT 阶段和目标 2：评估提供者和 家长愿意随机分组应答者以评估磨合期和 随机化。实现这些目标尤为重要，因为使用正式的 N-of-1 试验 将设计作为并行组 RCT 的磨合是一种独特且前沿的方法。完成这些后 目标，该试点项目将详细了解参与者能够完成的程度 N-of-1 试验将提供被确定为“反应者”的患者百分比的数据。这将使更多 准确评估进入平行组随机对照试验阶段的可用样本量。飞行员 还将提供确定磨合和并行之间的预期退出率所需的数据 由于不愿意将呋塞米或安慰剂的“反应者”随机化而进行分组 RCT 阶段。一起这个 信息将使有关更大试验样本量和 N-of-1 磨合设计的明智决策成为可能 阶段，这对于其他利尿剂和 BPD 管理策略的规划研究具有价值。