Interpretation and Utility of Novel Composite Structural Endpoints of Cumulative Damage and Disease Activity in Knee Osteoarthritis

膝骨关节炎累积损伤和疾病活动的新型复合结构终点的解释和应用

• 批准号: 10408670
• 负责人: Jeffrey B Driban
• 金额: $ 52.54万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408670
• 关键词: Address; Adult; Biological Factors; Biological Markers; Body mass index; Bone Marrow; Cartilage; Clinical; Clinical Trials; Collaborations; Data; Databases; Degenerative polyarthritis; Disease; Disease Progression; Drug Evaluation; Enrollment; Evaluation Research; Feedback; Funding; Goals; Image; Intervention; Joints; Knee; Knee Osteoarthritis; Lesion; Letters; Logistic Models; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Methods; Modeling; Modification; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outcome; Pain; Participant; Patient Outcomes Assessments; Patient-Focused Outcomes; Patients; Performance; Persons; Population; Process; Prognostic Marker; ROC Curve; Replacement Arthroplasty; Research; Research Project Grants; Resources; Sampling; Sampling Studies; Severities; Standardization; Strategic Planning; Symptoms; Synovitis; Teleconferences; Testing; Therapeutic; Time; Translating; Uncertainty; United States; United States Food and Drug Administration; Visit; Work; articular cartilage; base; case control; design; disability; early phase trial; effective therapy; effusion; end stage disease; imaging biomarker; improved; informant; joint injury; knee replacement arthroplasty; novel; novel therapeutics; pain reduction; phase III trial; predictive marker; programs; radiological imaging; repository; sex; success; walking speed

The United States Food and Drug Administration (FDA) recognizes osteoarthritis as a serious disease with an unmet need for therapies that slow, stop, or reverse joint damage. A challenge to testing new therapies is the lack of a comprehensive definition of disease progression that incorporates multiple structural changes. Another challenge is not knowing how much change in a structural measure would reflect meaningful benefit or worsening to a patient. Magnetic resonance (MR) imaging has great potential to address these critical gaps. However, no-one has developed an MR-based composite outcome that reflects multiple structural aspects (“whole-knee”) of knee osteoarthritis progression and is sensitive to change. This remains a critical technological obstacle to testing and developing new therapies. We recently tackled these barriers and found that structural measures of knee osteoarthritis progression can be summarized as: 1) cumulative damage (quantitative articular cartilage damage throughout a knee; relates to radiographic progression), and 2) disease activity (quantitative bone marrow lesions and effusion-synovitis volumes; relates to pain progression). The critical next steps are to demonstrate these outcomes are valid and useful predictive biomarkers of KOA progression by determining 1) how much change in each measure translates to indicators of clinically meaningful improvement or worsening and 2) the discriminative performance of each composite measure. We will accomplish this by assessing annual MR images in 3 nested case-control samples to determine the magnitude of change in cumulative damage and disease activity that predict changes in patient-reported outcomes (Aim 2) and walking speed (Aim 3), and knee replacement (Aim 4) across biological factors (e.g., sex). To achieve our goal, we will quantify 1- or 2-year change in articular cartilage as well as bone marrow lesions and effusion-synovitis volume on MR images for 5,270 knee visits. We will then determine the amount of change in cumulative damage or disease activity that relates to these outcomes during the same time period. We will also test how much change in these measures differentiates adults who will receive a knee replacement. Finally, we will test whether cumulative damage and disease activity will reliably predict changes in patient-centered outcomes across sex, body mass index, radiographic severity, and duration of observation period. This study will support an application for approval of these structural endpoints as predictive biomarkers for KOA progression, which could greatly improve the chance of success for clinical trials testing disease-modifying therapies for knee osteoarthritis.

美国食品药品监督管理局（FDA）认为骨关节炎是一种严重的疾病 未满足的疗法需要缓慢，停止或反向关节损伤。测试新疗法的挑战是 缺乏对疾病进展的全面定义，该定义融合了多种结构性变化。 另一个挑战是不知道结构措施中有多少变化将反映有意义的收益或 病人恶化。磁共振（MR）成像具有解决这些关键差距的巨大潜力。 但是，没有人开发出基于MR的复合结果，反映了多个结构方面 （“全膝盖”）膝关节骨关节炎的进展，对变化很敏感。这仍然是关键 测试和开发新疗法的技术障碍。我们最近解决了这些障碍，发现 膝关节骨关节炎进展的结构测量可以总结为：1）累积损害 （整个膝盖的定量关节软骨损伤；与影像学进展有关）和2）疾病 活性（定量的骨髓病变和积液 - 串联炎的体积；与疼痛进展有关）。 关键的下一步是证明这些结果是KOA的有效且有用的预测生物标志物 通过确定1）每种措施的变化转化为临床指标 有意义的改进或令人担忧的2）每个复合测量的判别性能。我们 将通过评估3个嵌套的病例对照样本中的年度MR图像来实现这一目标，以确定 预测患者报告的变化的累积损害和疾病活动的变化大小 结果（AIM 2）和步行速度（AIM 3）和膝盖置换（AIM 4）跨生物学因素（例如，例如， 性别）。为了实现我们的目标，我们将量化关节软骨和骨髓的1或2年变化 MR图像的病变和积液 - 串联炎，可进行5,270个膝盖探访。然后，我们将确定金额 与这些结果相关的累积损害或疾病活动的变化 时期。我们还将测试这些措施的变化，使成年人区分开了膝盖 替代品。最后，我们将测试累积损害和疾病活动是否可以可靠地预测变化 在性别，体重指数，射线照相严重程度和观察持续时间的以患者为中心的结果中 时期。这项研究将支持批准这些结构终点为预测的申请 KOA进展的生物标志物，这可以大大提高临床试验测试成功的机会 膝关节骨关节炎的疾病改良疗法。