Precision Medicine Approach to Vitamin D3 Administration in Critical Illness

危重疾病维生素 D3 给药的精准医学方法

基本信息

批准号：
10444999
负责人：
David Evan Leaf
金额：
$ 44.34万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10444999
关键词：
25-hydroxyvitamin D Acute Acute Disease Acute Renal Failure with Renal Papillary Necrosis Acute Respiratory Distress Syndrome Adipose tissue Affect Ancillary Study Animal Model Anti-Inflammatory Agents Archives Attenuated Binding Binding Proteins Biochemical Blood Circulation CYP27B1 gene Catabolism Cessation of life Cholecalciferol Clinical Complication Critical Illness DNA Data Development Dihydroxycholecalciferols Dose Drug Kinetics Early treatment Enrollment Enteral Enterocytes Enzymes Exocrine pancreatic insufficiency Fibroblasts Funding Future Genes Genetic Polymorphism Hormonal Hormones Hospitals Impairment Incidence Kidney Kidney Diseases Letters Link Liver Medical Genetics Metabolism National Heart, Lung, and Blood Institute Nature Obesity Osteocytes Parents Patients Placebos Plasma Play Population Property Publishing Randomized Randomized Controlled Trials Reporting Risk Role Sampling Severities Severity of illness Shock Small Intestines Somatotropin Specific qualifier value Stimulus Testing Therapeutic Agents Treatment Efficacy Variant Vitamin D Vitamin D3 Receptor absorption base chronic liver disease clinical decision-making clinically actionable clinically relevant cost efficient design effective therapy epidemiology study fibroblast growth factor 23 heme oxygenase-1 high risk immunoregulation improved outcome member mortality motility disorder organ injury patient population precision medicine preclinical study prevent primary endpoint response secondary endpoint treatment response treatment trial

项目摘要

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.

项目概要急性呼吸窘迫综合征（ARDS）是危重患者常见且具有破坏性的并发症疾病，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并减轻动物模型中的急性器官损伤。随机对照试验（随机对照试验）正在进行中，以测试服用维生素 D3 (vit D3) 是否可以改善危重患者的预后有患ARDS的风险。然而，由于危重疾病的异质性，患者特定因素可能会发挥作用在决定对维生素 D3 的反应中发挥着重要作用。我们将使用精准医学方法来研究决定危重疾病中维生素 D3 给药反应的临床、遗传和生化因素。该提案是 NHLBI 资助的维生素 D 项目的一项辅助研究，旨在通过利用维生素 D 来改善预后早期治疗 (VIOLET) 试验是一项正在进行的多中心随机对照试验，招募了 3000 名处于高危状态的危重患者 ARDS 和死亡的风险。患者被随机分配接受单次肠内剂量 540,000 I.U.。维特 D3 或安慰剂来测试 vit D3 是否可以降低 90 天死亡率和急性器官损伤。 VIOLET 正在存档第 0 天来自所有 3000 名患者的血浆和 DNA，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 名患者身上收集血浆（目标 1）并利用现有样本（目标 2 和 3）检验以下假设。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疾病中维生素 D3 给药的药代动力学反应。我们将测试是否更大疾病严重程度（较高的 SOFA 评分）、肥胖以及急性或慢性肝脏或肾脏疾病减弱第 0 天至第 3 天血浆 25-羟基维生素 D (25D) 和 1,25-二羟基维生素 D (1,25D) 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 靶基因中的基因可识别更有可能发生以下情况的患者群体：维生素 D3 给药的益处，通过 90 天死亡率（主要终点）和急性器官损伤进行评估（次要终点）。在目标 3 中，我们将研究是否降低血浆成纤维细胞生长因子 23 水平，一种骨细胞衍生激素，可抑制 25D 向 1,25D 的转化，更能识别患者群体通过 90 天死亡率（主要终点）和急性器官评估，可能受益于 vit D3 给药伤害（次要终点）。开发用于治疗危重疾病的维生素 D3 的精准医学方法可能会产生以下效果：通过帮助临床决策和设计提供直接和可操作的临床影响维生素 D 代谢物治疗危重疾病的未来试验。