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: 10563130
• 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/10563130
• 关键词: Adrenal Glands; Adrenal gland hypofunction; Affect; American; Asthma; Autoimmune; Autoimmune Diseases; Award; Biological; Central Nervous System; Cessation of life; Chronic Obstructive Pulmonary Disease; Classification; Clinical; Clinical Sciences; Clinical Trials; Clinical Trials Design; Data; Dimensions; 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; Neurologic; Opioid; Oral; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Population; Prednisone; Prospective cohort; Protocols documentation; Publications; Publishing; Qualifying; Recommendation; 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; brain fog; care providers; career; career development; central sensitization; clinical phenotype; cohort; design; experience; functional improvement; high risk; immune activation; immunomodulatory therapies; improved; 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; randomized, clinical trials; 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：类风湿关节炎(RA)患者通常使用糖皮质激素(GCs)，尽管他们 毒性和不良症状的风险，当它们逐渐减少。这些症状构成了GC的主要障碍 对许多人来说是缩减，但对其他人来说是最小的或可以容忍的。临床医生无法预测患者将如何 应对GC剂量减少，并在缩减GC时依靠反复尝试，鼓励延长GC 曝光。基于患者表型的个性化医疗是RA管理的基石，但 目前的GC缩减战略仍是“一刀切”。 意义/影响：此应用程序提出职业发展和研究计划，以表征和 退伍军人类风湿关节炎患者对GC剂量减少的表型反应。这项研究议程与 临床科学研究与发展优先研究侧重于个体化治疗反应和 优化治疗。短期内，这项提案的结果将导致优秀奖提案 针对特定表型量身定做的测试GC缩减协议，按顺序多分配随机进行 临床试验(SMART)。从长远来看，华莱士博士将扩展这一研究线，使a)GC逐渐减少 退伍军人常见的其他疾病(如慢性阻塞性肺疾病、哮喘、痛风等)。b) 指导优化的数据有限的其他高风险治疗方案(例如生物药物、阿片类药物)。 华莱士博士是VHA风湿病专家和研究调查员，致力于改进治疗方法 退伍军人使用高风险药物的结果她的长期目标是成为一名独立的医生- 科学家专注于开发个性化的序贯治疗策略，以优化患者的用药 退伍军人。 创新：拟议的工作将把个性化医学方法应用于GC缩减，以了解 为什么，对谁来说，当前的GC缩减策略失败了。短期内，这一研究领域将产生新的 关于退伍军人类风湿性关节炎相关症状的病因和处理的假说 作为关于GC响应表型和相关效应大小的关键数据。从长远来看，这项工作将告诉其他人 指导VHA内跨医学专科优化高风险药物的创新试验。 具体目标：以RA退伍军人为测试对象，本提案旨在(1)评估对(A)的反应 15天和6个月的GC剂量减少策略；(2)确定患者的多维表型 对GC剂量减少的反应，可用于制定量身定制的GC缩减策略(SA2)。 培训目标：华莱士博士和她的指导团队制定了一个有针对性的课程计划， 研讨会、定向阅读和有指导的研究，将为她提供必要的培训：a) 选择和解释衡量治疗变化的适当终点；b)量化方法 临床表型鉴定所需的；c)临床试验设计和分析，并接受SMART和 适应性方法论。 来自AIMS的交付成果：提议的AIMS将使华莱士博士准备撰写和提交一份功绩建议书 (4年级)使用智能方法在患有RA的退伍军人中测试定制的GC缩减策略。除了……之外 除了会议报告和出版物，她将与一系列合作伙伴合作传播她的研究成果 整个VHA的调查结果，并制定战略，以实施她的工作和最大限度地发挥影响。