Using SMART Design to Develop Dynamic Treatment Regimens for Glucocorticoid Tapering

使用 SMART 设计开发糖皮质激素逐渐减量的动态治疗方案

• 批准号: 10367543
• 负责人: Beth Ilene Wallace
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367543
• 关键词: Adrenal Glands; Adrenal gland hypofunction; Affect; American; Asthma; Autoimmune; Autoimmune Diseases; Award; Biological; Cessation of life; Chronic Obstructive Pulmonary Disease; Classification; Clinical; Clinical Sciences; Clinical Trials; Clinical Trials Design; Custom; Data; Dose; Endocrine; Etiology; Fatigue; Female; Fracture; Funding; Future; Glucocorticoids; Goals; Gout; Guidelines; Hyperalgesia; Immune; Individual; Infection; Inflammatory Arthritis; Linear Regressions; Link; Logistic Regressions; Measures; Mentors; Mentorship; Methodology; Methods; Minor; Moods; Myalgia; Myocardial Infarction; Neuraxis; Neurologic; Opioid; Oral; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Population; Prednisone; Prospective cohort; Protocols documentation; Publications; Publishing; Randomized Clinical Trials; Reading; Research; Research Personnel; Research Priority; Rheumatoid Arthritis; Risk; Running; Scientist; Sequential Treatment; Statistical Models; Steroids; Stroke; Symptoms; Techniques; Testing; Toxic effect; Training; Treatment Protocols; Treatment outcome; Uncertainty; United States; Veterans; Veterans Health Administration; Work; Writing; arm; base; brain fog; care providers; career; career development; central sensitization; clinical phenotype; cohort; design; experience; high risk; immune activation; immunomodulatory therapies; improved; improved functioning; innovation; joint injury; medical specialties; military veteran; multimodality; opioid use disorder; patient response; patient tolerability; personalized approach; personalized medicine; predicting response; predictive signature; primary outcome; programs; prospective; randomized trial; research and development; response; rheumatologist; success; symposium; treatment optimization; treatment response; treatment strategy

Background: Patients with rheumatoid arthritis (RA) commonly use glucocorticoids (GCs) despite their toxicity and the risk of adverse symptoms when they are tapered. Such symptoms pose a major barrier to GC tapering for many, but are minimal or well-tolerated by others. Clinicians cannot predict how a patient will respond to GC dose reduction and rely on trial and error when tapering GCs, encouraging extended GC exposure. Personalized medicine based on patient phenotyping is a cornerstone of RA management, yet current GC tapering strategies remain “one size fits all”. Significance/Impact: This application proposes a career development and research plan to characterize and phenotype responses to GC dose reduction among Veterans with RA. This research agenda is well-aligned with Clinical Science Research and Development priority research focus on individual treatment response and treatment optimization. In the short-term, the results of this proposal will lead to a Merit award proposal to test GC tapering protocols tailored to specific phenotypes, in a sequential multi-assignment randomized clinical trial (SMART). Long-term, Dr. Wallace will expand this line of research to personalize a) GC tapering in other conditions common among Veterans (e.g. chronic obstructive pulmonary disease, asthma, gout, etc). b) other high-risk treatment regimens where data to guide optimization are limited (e.g. biologic drugs, opioids). Dr. Wallace is a VHA rheumatologist and research investigator who is committed to improving treatment outcomes for Veterans using high-risk medications Her long-term goal is to become an independent physician- scientist focused on developing personalized sequential treatment strategies to optimize medication use in the Veteran population. Innovation: The proposed work will apply personalized medicine approaches to GC tapering to understand why, and for whom, current GC tapering strategies fail. Short-term, this line of research will generate new hypotheses surrounding etiology and management of GC taper-related symptoms in Veterans with RA, as well as critical data on GC response phenotypes and associated effect sizes. Long-term, this work will inform other innovative trials to guide optimization of high-risk medications across medical specialties within VHA. Specific Aims: Focusing on Veterans with RA as a test case, this proposal aims to (1) Evaluate response to (a) 15-day and (b) 6-month GC dose reduction strategies; (2) Identify multi-dimensional phenotypes of patient response to GC dose reduction, that can be used to develop tailored GC tapering strategies (SA2). Training Aims: Dr. Wallace and her mentorship team have developed a program of targeted coursework, seminars, directed readings, and mentored research that will provide her with necessary training in: a) selecting and interpreting appropriate endpoints for measuring treatment change; b) quantitative methods required for clinical phenotyping; c) clinical trial design and analysis, with specific training in SMART and adaptive methodologies. Deliverables from Aims: The proposed aims will prepare Dr. Wallace to write and submit a Merit proposal (Year 4) that uses SMART methods to test tailored GC tapering strategies in Veterans with RA. In addition to conference presentations and publications, she will work with an array of partners to disseminate her research findings throughout VHA and develop strategies to implement her work and maximize impact.

背景：类风湿性关节炎（RA）患者通常使用糖皮质激素（GC），尽管他们 毒性和逐渐减少时出现不良症状的风险。这些症状构成GC的主要障碍 对许多人来说逐渐减少，但其他人则最小或耐受性良好。临床医生无法预测患者的情况 对 GC 剂量减少做出反应，并在逐渐减少 GC 时依靠反复试验，鼓励延长 GC 接触。基于患者表型的个性化医疗是 RA 管理的基石，但 当前的 GC 逐渐减少策略仍然是“一刀切”。 意义/影响：本申请提出了职业发展和研究计划来描述和 患有 RA 的退伍军人对 GC 剂量减少的表型反应。该研究议程与 临床科学研究和发展优先研究重点关注个体治疗反应和 治疗优化。在短期内，该提案的结果将导致一项优异奖提案 在顺序多任务随机测试中测试针对特定表型定制的 GC 逐渐减量方案 临床试验（SMART）。从长远来看，华莱士博士将扩展这一研究领域，以个性化 a) GC 逐渐减少 退伍军人中常见的其他疾病（例如慢性阻塞性肺病、哮喘、痛风等）。 b) 其他高风险治疗方案，指导优化的数据有限（例如生物药物、阿片类药物）。 Wallace 博士是 VHA 风湿病学家和研究调查员，致力于改善治疗 使用高风险药物的退伍军人的结果她的长期目标是成为一名独立医生- 科学家专注于开发个性化序贯治疗策略，以优化药物使用 退伍军人人口。 创新：拟议的工作将应用个性化医学方法来减少 GC 剂量，以了解 当前 GC 逐渐减少策略为何失败以及对谁而言失败。短期内，这方面的研究将产生新的 围绕 RA 退伍军人的 GC 减量相关症状的病因学和治疗的假设，以及 作为 GC 响应表型和相关效应大小的关键数据。从长远来看，这项工作将为其他人提供信息 指导 VHA 内各医学专业高风险药物优化的创新试验。 具体目标：以 RA 退伍军人为测试案例，该提案旨在 (1) 评估对 (a) 的反应 15 天和 (b) 6 个月 GC 剂量减少策略； (2) 识别患者多维表型 对 GC 剂量减少的反应，可用于开发定制的 GC 逐渐减少策略 (SA2)。 培训目标：华莱士博士和她的导师团队制定了一个有针对性的课程计划， 研讨会、定向阅读和指导研究将为她提供以下方面的必要培训：a) 选择和解释适当的终点来衡量治疗变化； b) 定量方法 临床表型分析所需； c) 临床试验设计和分析，经过 SMART 和 适应性方法。 目标的可交付成果：拟议的目标将使华莱士博士准备好撰写并提交一份优点提案 （第 4 年）使用 SMART 方法测试患有 RA 退伍军人的定制 GC 逐渐减少策略。此外 会议演讲和出版物，她将与一系列合作伙伴合作传播她的研究 整个 VHA 的调查结果并制定战略来实施她的工作并最大限度地发挥影响力。