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（GC），尽管他们 毒性和不良症状的风险，当他们逐渐减少。这些症状构成了GC的主要障碍 对许多人来说是逐渐变细的，但对其他人来说是最小的或耐受良好的。临床医生无法预测患者将如何 对GC剂量减少有反应，在逐渐减少GC时依赖于试验和错误，鼓励延长GC exposure.基于患者表型的个性化药物是RA管理的基石，但 目前的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，以表征和 RA退伍军人对GC剂量减少的表型反应。该研究议程与 临床科学研究和开发优先研究重点是个体治疗反应， 治疗优化在短期内，这一提案的结果将导致一个优异奖提案， 在一个连续的多分配随机试验中， 临床试验（SMART）。从长远来看，华莱士博士将扩大这一系列的研究，以个性化a）GC逐渐减少， 退伍军人中常见的其他疾病（如慢性阻塞性肺病、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）。 博士华莱士是一个VHA风湿病学家和研究调查员谁是致力于改善治疗 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，以优化药物使用， 退伍军人 创新：拟议的工作将应用个性化的医学方法来GC逐渐减少，以了解 为什么，以及对谁来说，目前的GC逐渐减少策略失败了。短期内，这一研究方向将产生新的 关于RA退伍军人中GC锥形相关症状的病因和管理的假设，以及 作为GC反应表型和相关效应量的关键数据。从长远来看，这项工作将告知其他 创新试验，以指导VHA内各医学专业的高风险药物的优化。 具体目标：以患有类风湿关节炎的退伍军人为测试案例，本提案旨在（1）评价对（a） 15-d和（B）6个月GC剂量减少策略;（2）识别患者的多维表型 对GC剂量减少的反应，可用于开发定制的GC递减策略（SA 2）。 培训目标：华莱士博士和她的导师团队已经制定了一个有针对性的课程计划， 研讨会，指导阅读，并指导研究，将为她提供必要的培训：a） 选择和解释用于测量治疗变化的适当终点; B）定量方法 c）临床试验设计和分析，并接受SMART方面的专门培训， 适应性方法。 目标中的可验证内容：拟定的目标将为Wallace博士编写并提交Merit提案做好准备 (Year 4）使用SMART方法来测试RA退伍军人中定制的GC逐渐减少策略。除了 会议演讲和出版物，她将与一系列合作伙伴传播她的研究 调查结果在整个VHA和制定战略，以实施她的工作，并最大限度地发挥影响。