Treat-to-Target Serum Urate versus Treat-to-Avoid Symptoms in Gout: A Randomized Controlled Trial (TRUST)

摘要 痛风是最常见的炎症性关节炎，影响超过900万美国成年人， 世界范围内的负担越来越重。尽管有大量的临床后果，痛风护理是不一致的， 证据基础的漏洞。异质性痛风治疗的主要贡献者是缺乏共识， 由于缺乏高水平的证据，实现目标血清尿酸盐（SU）的价值。风湿病 指南强调治疗靶向血清尿酸盐（TTT-SU）方法（例如，SU <6 mg/dL，尿酸盐低于 饱和点）;然而，由于缺乏证据，在降低尿酸盐期间甚至没有测量SU 在初级保健实践中，绝大多数痛风患者的治疗，其中>90%的痛风护理发生。我们 旨在通过动员风湿病学家和主要研究人员， 护理提供者（PCP）。此外，痛风是一种代谢性疾病，伴有心肌梗死的高风险。 糖尿病，慢性肾脏疾病和过早死亡，尽管痛风是否 导致了这些结果。通过降低SU来去除草酸盐晶体沉积， 痛风性炎症，可能是通过钝化炎性体途径。然而，目前尚不清楚是否降低SU 减少肾损伤，更好地控制血糖或降低心血管风险。 NIH的资助使我们能够在2018年与PCP和风湿病学家召开会议（R13 AR 073116）， 检查现有的数据，确定争议，并征求必要的信息，以填补 关键证据缺口根据这次会议的信息，我们在2020年获得了资金（AR 076077），以计划 随机对照试验（RCT）。在过去的一年半里，我们开展了一些重要活动， 所有相关利益攸关方。一个改良的德尔菲小组，包括痛风患者，护士和医生助理， PCP和流变学家就关键方案决策达成共识。模拟招聘活动 使我们能够测试和完善可行的程序，这将导致成功的预筛选，筛选， 在拟定的多中心RCT期间招募患者，有以下两个目的。 目的1）对痛风合并高尿酸血症（HU）患者进行TTASx和TTT-SU的随机对照试验。 我们已经制定了一个所有相关利益相关者都能接受的试验方案， 主要假设TTT-SU策略导致痛风发作（主要结局）显著少于 比TTASx随访2年。为了确保平衡和普遍性，我们将从PCP招募患者 实践目的2）探讨降低SU对肾功能、血糖和血压的影响 在随机对照试验的痛风患者中。相应的假设是，将SU降低到更大 与TTASx相比，TTT-SU组的程度将导致： 滤过率; B）降低HbA 1c;和c）改善痛风患者的血压。

ABSTRACT Gout is the most common inflammatory arthritis, affecting more than 9 million American adults, with a disease burden rising worldwide. Despite substantial clinical consequences, gout care is inconsistent, with considerable gaps in the evidence base. The primary contributor to heterogeneous gout care is a lack of agreement about the value of achieving a target serum urate (SU), due to a lack of high-level evidence. Rheumatology guidelines emphasize a treat to target serum urate (TTT-SU) approach (e.g., SU <6 mg/dL, a urate sub- saturation point); however, citing the absence of evidence, SU is not even measured during urate-lowering therapy in the vast majority of gout patients in primary care practice, where >90% of gout care occurs. We aim to generate high-level evidence to resolve the guideline conflict by mobilizing rheumatologists and primary care providers (PCPs). Furthermore, gout is a metabolic condition complicated by a high risk of myocardial infarction, diabetes, chronic kidney disease, and premature death, although it remains unknown whether gout causally leads to these outcomes. Removing monosodium urate crystal deposition by lowering SU can reduce gouty inflammation, likely by blunting the inflammasome pathway. However, it is unknown whether lowering SU results in less kidney damage, better glycemic control, or reduced cardiovascular risk. NIH funding allowed us to convene a conference in 2018 (R13AR073116) with PCPs and rheumatologists to examine the existing data, define the controversies, and elicit input on the necessary information to fill the critical evidence gap. Informed by this conference, we received funding in 2020 (AR076077) to plan a randomized controlled trial (RCT). During the past 1.5 years, we carried out key activities to gain insights from all relevant stakeholders. A modified Delphi Panel, including gout patients, nurses and physician assistants, PCPs, and rheumatologists, came to consensus regarding key protocol decisions. Mock recruitment activities allowed us to test and refine feasible procedures which will lead to successful pre-screening, screening, and patient recruitment during the proposed multi-site RCT with the following two aims. Aim 1) To conduct a RCT comparing TTASx with TTT-SU among patients with gout and hyperuricemia (HU). We have developed a trial protocol acceptable for all relevant stakeholders that will effectively answer the primary hypothesis that a TTT-SU strategy results in significantly fewer gout flares (primary outcome) over a two-year follow-up than TTASx. To ensure equipoise and generalizability, we will recruit patients from PCP practices. Aim 2) To test the effects of lowering SU on kidney function, glycemic status, and blood pressure among patients with gout enrolled in the RCT. The corresponding hypotheses are that lowering SU to a greater extent in the TTT-SU arm compared with TTASx will result in: a) slower decline in estimated glomerular filtration rate; b) lower HbA1c; and c) improved blood pressure in gout patients.