DDT-BMQ-00086 End-Stage Knee Osteoarthritis as a Prognostic Biomarker for Knee Osteoarthritis Trials

项目摘要FDA承认骨性关节炎是一种严重的疾病，因为它是 疼痛、残疾和关节置换术，几乎没有有效的治疗方法，也没有人接受任何治疗来减少其总体 进步。开发有效疗法的障碍包括未能丰富研究样本， 进展和缺乏结构性终点，这些终点可以可靠地预测疼痛减轻、功能增强或 终末期疾病的时间延长了“。具体地说，我们缺乏一个结构性终点或严重程度的代理指标 膝骨性关节炎。接受膝关节置换术通常被用作以患者为中心的膝关节终点 骨关节炎，但这与膝骨性关节炎严重程度的生物学测量有高度可变的关系 以及对外部影响的强烈依赖(例如，期望、精神和身体上的准备 手术)。这些方面使得膝关节置换术作为一致的疾病严重程度终点不可靠。另外， 作为结果，膝关节置换的频率很低，这要求样本大小对于大多数临床试验来说是不可行的。 为了克服这些障碍，我们引入了反映“终末期膝骨性关节炎”的复合定义。 (EsKOA)，它将患者报告的结果与结构性严重性措施相结合，以消除 外在因素对此疾病状态的影响。我们一致同意的专家小组对此进行了调整 来自膝关节置换的适宜性算法的定义，该算法被进一步开发和验证 流行病学研究。简而言之，esKOA出现在患有1)严重放射学骨关节炎(Kellgren- 劳伦斯[KL]等级=4)中重度疼痛或2)KL等级和4)剧烈或重度疼痛 以及有限的机动性或不稳定。FDA药物评价和研究中心接受了我们的申请 将esKOA注册到他们的Biomarker资格认证计划中，并建议将其用作“预测者” 在诊断为膝骨性关节炎的受试者的临床试验中用于识别患者的生物标志物面板 谁可能经历长期的疾病进展…需要做膝关节置换手术“。致信地址 关键的下一步，我们将使用基于膝盖的数据分析来自骨关节炎倡议的数据(8888膝 从4,479人)，这是一个纵向的多中心观察队列，明确地设计为发展膝盖 骨关节炎生物标记物。具体地说，我们的目标是确定esKOA的每个组件及其 拟议的阈值“与疾病向esKOA[目标1]的进展有关，以及它们[和esKOA]如何 有助于确定进展或不进展为膝关节置换的患者[目标2]“。 此外，我们将评估“生物标记物和临床结果评估的复合体” 组件可能不必要地复杂“，并且可以简化。这项提议将进一步推动 膝关节骨性关节炎作为未来膝关节置换预后生物标志物的研究进展。这一预测生物标志物将 公开提供以丰富临床试验或早期试验的研究样本，以证明 干预的治疗潜力。

PROJECT SUMMARY The FDA recognizes osteoarthritis as a serious disease since it is a leading cause of pain, disability, and arthroplasty with few effective treatments and none accepted to reduce its overall progression. Barriers to developing effective therapies include failure to enrich study samples with people likely to progress and an absence of structural endpoints that “reliably predict reduced pain, increased function, or prolonged time to end-stage disease”. Specifically, we lack a structural endpoint or proxy indicator of severe knee osteoarthritis. Receipt of a knee replacement is often used as a patient-centered endpoint for knee osteoarthritis, but this has a highly variable relationship with biological measures of knee osteoarthritis severity and a strong dependence on extraneous influences (e.g., expectations, mental and physical readiness for surgery). These aspects render knee replacements unreliable as a consistent disease severity endpoint. Also, the low frequency of knee replacement as an outcome requires sample sizes infeasible for most clinical trials. To overcome these barriers, we introduced a composite definition reflecting “end-stage knee osteoarthritis” (esKOA), which combines patient-reported outcomes with structural severity measures to eliminate the influence of extraneous factors in designating this disease status. Our consensus panel of experts adapted this definition from an appropriateness algorithm for knee arthroplasty that was further developed and validated for epidemiologic studies. In brief, esKOA is present in a knee with 1) severe radiographic osteoarthritis (Kellgren- Lawrence [KL] grade = 4 out of 4) with moderate-intense pain or 2) KL grade < 4 with intense or severe pain and limited mobility or instability. The FDA Center for Drug Evaluation and Research accepted our application to enroll esKOA into their Biomarker Qualification Program with a proposed context of use as a “prognostic biomarker panel for use in clinical trials with subjects with a diagnosis of knee osteoarthritis to identify patients who are likely to experience long-term disease progression…requiring knee replacement surgery”. To address the critical next steps, we will use knee-based analyses of data from the Osteoarthritis Initiative (8,888 knees from 4,479 people), which is a longitudinal multicenter observational cohort explicitly designed to develop knee osteoarthritis biomarkers. Specifically, we will aim to determine how each component of esKOA and their proposed thresholds “relate to disease progression towards esKOA [Aim 1] and how they [and esKOA] may contribute to identification of patients who progress or will not progress to knee replacement [Aim 2]”. Furthermore, we will assess whether a “composite made of both biomarker and clinical outcome assessment components may be unnecessarily complicated” and could be simplified. This proposal will further the development of esKOA as a prognostic biomarker for future knee replacement. This prognostic biomarker will be made publicly available to enrich a study sample for clinical trials or in early-phase trials to demonstrate an intervention’s therapeutic potential.