Precision Medicine Approach to Vitamin D3 Administration in Critical Illness

项目摘要 急性呼吸窘迫综合征（ARDS）是危重病患者常见的严重并发症， 疾病和预防ARDS的有效疗法是有限的。维生素D代谢物具有强效 免疫调节作用和减轻动物模型中急性器官损伤。随机对照试验 正在进行随机对照试验（RCT），以测试维生素D3（vit D3）给药是否能改善危重患者的预后 有ARDS的风险。然而，由于危重病的异质性，患者特异性因素可能起作用， 在决定对维生素D3的反应中起主要作用。我们将使用精确医学方法来研究 临床、遗传和生化因素决定了危重病患者对维生素D3的反应。 该提案是NHLBI资助的维生素D的辅助研究，以通过利用 早期治疗（VIOLET）试验，一项正在进行的多中心RCT，正在招募3000名高风险的危重患者。 ARDS和死亡的风险。患者被随机分配接受540，000 I.U.的单次肠内剂量。维生 D3或安慰剂，以测试维生素D3是否降低90天死亡率和急性器官损伤。VIOLET正在归档 在第0天来自所有3000名患者的血浆和DNA，以及在第3天来自前300名患者的血浆。我们 建议在第3天从另外500名患者（目标1）中采集血浆，并利用现有样本 (Aims（2）检验下列假设。 在目标1中，我们将使用第0天和第3天的配对血浆样本（n=400）来研究临床因素 影响危重病患者对维生素D3给药的药代动力学反应。我们将测试 疾病严重程度（较高的SOFA评分）、肥胖和急性或慢性肝脏或肾脏疾病会减弱 从第0天到第3天，血浆25-羟基维生素D（25 D）和1，25-二羟基维生素D（1，25 D）水平增加， 接受维生素D3的患者。在目标2中，我们将研究是否预先指定的常见多态性， 影响维生素D代谢的基因或维生素D靶基因识别出更有可能 通过90天死亡率（主要终点）和急性器官损伤评估的维生素D3给药获益 （次要终点）。在目标3中，我们将研究降低成纤维细胞生长因子-23的血浆水平， 一种抑制25 D转化为1，25 D的骨细胞衍生激素， 可能从维生素D3给药中获益，通过90天死亡率（主要终点）和急性器官功能衰竭评估 损伤（次要终点）。 开发一种精确的医学方法来治疗危重病中的维生素D3给药， 通过帮助为临床决策和设计提供信息， 维生素D代谢物在危重病中的未来试验。

PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) is a common and devastating complication of critical illness, and effective therapies to prevent ARDS are limited. Vitamin D metabolites have potent immunomodulatory effects and attenuate acute organ injury in animal models. Randomized controlled trials (RCTs) are ongoing to test whether vitamin D3 (vit D3) administration improves outcomes in critically ill patients at risk of ARDS. However, due to the heterogeneous nature of critical illness, patient-specific factors likely play a major role in determining response to vit D3. We will use a precision medicine approach to investigate the clinical, genetic, and biochemical factors that determine response to vit D3 administration in critical illness. This proposal is an ancillary study to the NHLBI-funded Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, an ongoing, multicenter RCT that is enrolling 3000 critically ill patients at high risk of ARDS and death. Patients are randomly assigned to receive a single enteral dose of 540,000 I.U. of vit D3 or placebo to test whether vit D3 reduces 90-day mortality and acute organ injury. VIOLET is archiving plasma and DNA from all 3000 patients on day 0, and plasma on day 3 from the first 300 patients. We propose to collect plasma on day 3 from an additional 500 patients (Aim 1) and to leverage existing samples (Aims 2 and 3) to test the following hypotheses. In Aim 1 we will use paired plasma samples (n=400) from days 0 and 3 to investigate the clinical factors that affect the pharmacokinetic response to vit D3 administration in critical illness. We will test whether greater severity-of-illness (higher SOFA score), obesity, and acute or chronic liver or kidney disease attenuate increases in plasma 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) levels from day 0 to 3 in patients who receive vit D3. In Aim 2 we will investigate whether pre-specified common polymorphisms in genes affecting vitamin D metabolism or in vitamin D target genes identify a patient population more likely to benefit from vit D3 administration, assessed by 90-day mortality (primary endpoint) and acute organ injury (secondary endpoint). In Aim 3, we will investigate whether lower plasma levels of fibroblast growth factor-23, an osteocyte-derived hormone that inhibits the conversion of 25D to 1,25D, identify a patient population more likely to benefit from vit D3 administration, assessed by 90-day mortality (primary endpoint) and acute organ injury (secondary endpoint). Development of a precision medicine approach to vit D3 administration in critical illness could have immediate and actionable clinical impact by helping to inform both clinical decision making and the design of future trials of vitamin D metabolites in critical illness.