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

DDT-BMQ-00086 末期膝骨关节炎作为膝骨关节炎试验的预后生物标志物

• 批准号: 10410084
• 负责人: Jeffrey B Driban
• 金额: $ 24.78万
• 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: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410084
• 关键词: DDT; BMQ; 00086; End; Stage

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.

项目摘要FDA认为骨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，没有人接受整体的总体 进展。开发有效疗法的障碍包括未能与可能的人丰富研究样本 进步和缺乏结构性终点，“可靠地预测疼痛，功能增加或 长时间到达终阶段疾病”。具体而言，我们缺乏严重的结构性终点或代理指标 膝盖骨关节炎。膝盖置换的收到通常用作以患者为中心的膝盖 骨关节炎，但这与膝盖骨关节炎严重程度的生物学测量有高度可变的关系 以及对无关影响的强烈依赖（例如，期望，心理和身体准备就绪 外科手术）。这些方面使膝盖替换不可靠，成为一致的疾病严重程度终点。还， 膝盖替代的低频作为结果，需要大多数临床试验的样本量不可行。 为了克服这些障碍，我们引入了一个反映“末期膝盖骨关节炎”的复合定义 （Eskoa），将患者报告的结果与结构严重程度措施相结合以消除 无关因素在设计这种疾病状态时的影响。我们共识的专家小组对此进行了改编 膝关节置换术的适当性算法的定义，该算法得到了进一步开发和验证 流行病学研究。简而 劳伦斯[KL]等级= 4）4）中度疼痛或2）kl <4 <4 以及有限的移动性或不稳定。 FDA药物评估与研究中心接受了我们的应用 将Eskoa注入其生物标志物资格计划，并用作“预后 生物标志物面板用于患有膝关节骨关节炎的受试者的临床试验中，以识别患者 谁可能会经历长期疾病进展……需要膝盖置换手术”。 接下来的关键步骤，我们将使用骨关节炎计划的基于膝盖的数据分析（8,888膝盖） 来自4,479人），这是一个纵向多中心观察队列，明确设计为发展膝盖 骨关节炎生物标志物。具体而言，我们将旨在确定Eskoa的每个组成部分及其如何 拟议的阈值“与疾病向Eskoa [AIM 1]相关的阈值以及它们[和Eskoa]如何可能 有助于鉴定进步或不会进展为膝盖替代的患者[AIM 2]”。 此外，我们将评估“由生物标志物和临床结果评估制成的复合材料 组件可能不必要的复杂”，可以简化。该提案将进一步进一步 Eskoa作为未来膝盖替代的预后生物标志物的发展。这个预后的生物标志物将 公开使用以丰富用于临床试验或早期试验的研究样本，以证明 干预的治疗潜力。