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：
10217234
负责人：
David Evan Leaf
金额：
$ 44.39万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217234
关键词：
25-hydroxyvitamin D Acute Acute Disease Acute Renal Failure with Renal Papillary Necrosis Adipose tissue Adult Respiratory Distress Syndrome 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.

项目摘要急性呼吸窘迫综合征（ARDS）是关键的常见且破坏性的并发症疾病和防止ARD的有效疗法受到限制。维生素D代谢产物有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（RCT）正在进行测试维生素D3（VIT D3）给药是否改善重症患者的预后有ARDS的风险。但是，由于重症疾病的异质性质，患者特异性因素可能会发挥作用确定对VIT D3的反应的主要作用。我们将使用精确的医学方法来调查临床，遗传和生化因素决定了对危重疾病中VIT D3的反应。该建议是对NHLBI资助的维生素D的辅助研究，以通过利用来改善预后早期治疗（紫罗兰色）试验是一种正在进行的多中心RCT，正在招募3000名重症患者 ARDS和死亡的风险。随机分配患者接受540,000 I.U.的单一肠剂量vit D3或安慰剂测试VIT D3是否降低了90天的死亡率和急性器官损伤。紫罗兰正在存档所有3000名患者的血浆和DNA，以及前300例患者的第3天血浆。我们建议在第3天从另外500名患者（AIM 1）收集血浆，并利用现有样品（目标2和3）测试以下假设。在AIM 1中，我们将使用第0天和第3天的配对等离子体样品（n = 400）来研究临床因素这会影响严重疾病中VIT D3给药的药代动力学反应。我们将测试是否更大严重性（较高的沙发评分），肥胖症，急性或慢性肝或肾脏疾病从第0天到3的等离子体25-羟基维生素D（25D）和1,25-二羟基维生素D（1,25D）水平接受VIT D3的患者。在AIM 2中，我们将研究是否预先指定的共同多态性影响维生素D代谢或维生素D靶基因的基因鉴定患者群体更有可能受益于VIT D3给药，通过90天死亡率（主要终点）和急性器官损伤评估（次要端点）。在AIM 3中，我们将研究成纤维细胞生长因子23的血浆水平是否降低抑制25d至1,25d的骨细胞衍生的激素，更多地识别患者人群可能受益于VIT D3给药，通过90天死亡率（主要终点）和急性器官评估伤害（次要终点）。开发一种在危害疾病中为VIT D3给药的精确医学方法可能有通过帮助临床决策和设计，立即且可行的临床影响维生素D代谢物在危重疾病中的未来试验。