Hydroxychloroquine for the Management of CVD in CKD

羟氯喹用于治疗 CKD 中的 CVD

• 批准号: 10038795
• 负责人: MARK S. SEGAL
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038795
• 关键词: Adverse event; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Area; Atherosclerosis; Autoimmune Diseases; Biochemical; Biological Markers; Blood Vessels; C-reactive protein; Cardiac; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Plaques; Carotid Atherosclerotic Disease; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Research; Congestive Heart Failure; Creatinine; Data; Diabetes Mellitus; Diagnosis; Disease; End stage renal failure; Endothelium; Enrollment; Evaluation; Event; Feasibility Studies; Funding; Future; General Population; Hospitalization; Human; Hydroxychloroquine; Hypertension; In Vitro; Incidence; Inflammation; Inflammatory; Intervention; Kidney; Magnetic Resonance Imaging; Measures; Metabolic syndrome; Monitor; Morbidity - disease rate; Myocardial Infarction; Outcome; Outcome Measure; Outcome Study; Patient Selection; Patients; Pharmaceutical Preparations; Physiologic pulse; Placebos; Population; Process; Randomized Controlled Trials; Refractory; Research; Role; Safety; Sample Size; Stenosis; Stroke; Structure; Surface; Therapeutic; Time; Veterans; base; cardiovascular risk factor; cohort; cost; design; effective therapy; efficacy study; endothelial dysfunction; epidemiologic data; in vivo; insight; insulin sensitivity; medication safety; mortality; novel therapeutics; population based; primary outcome; risk stratification; safety outcomes; secondary outcome; trend; vascular factor

Cardiovascular disease (CVD) is the most prominent cause of morbidity and mortality among patients with chronic kidney disease (CKD), and end stage kidney disease (ESKD). Unfortunately at the present time, we do not have an effective treatment to reduce the high CVD mortality in these populations. Accelerated atherosclerosis, inflammation, and vascular stiffness are prominent factors contributing to CVD in CKD. Interventions that can effectively counter these factors may provide significant benefits for the management of CVD in CKD. Hydroxychloroquine (HCQ) is an inexpensive and safe anti-inflammatory drug that has been in clinical use for over 4 decades even in patients with CKD and ESKD. In recent times, multiple in vitro, in vivo, and human cohort based data have shown that HCQ benefits multiple parameters of CVD, including inflammation, endothelial function, metabolic syndrome, insulin sensitivity and atherosclerosis. Recently we through our animal validated that HCQ indeed has significant anti-atherosclerosis and vasculoprotective effects in CKD milieu. We further conducted a small, human, feasibility study that shows a potential for HCQ on parameters relevant to CVD in CKD. The next step requires evaluation of HCQ's role for the treatment of CVD in CKD. However, in the absence of a universally agreed-on surrogate for CVD, a proof-of-concept clinical study needed to validate the anti- atherosclerosis and vasculoprotective potential of HCQ in CKD. We propose such a study that will enroll 90 albuminuric, stage 3b CKD subjects in a randomized controlled trial (RCT) with 1:1 allocation (HCQ : placebo), stratified by their diabetes status, and treat for a duration of 18 months. We will examine the effects of HCQ on structural, functional, and biochemical measures of atherosclerosis and CVD. Specific Aim (SA) 1 will evaluate the ability of HCQ, compared to placebo, to slow the progression, or reverse atherosclerosis. We will evaluate the progression of carotid atherosclerosis with a non-contrast MRI performed at baseline and after 9 and 18 months of treatment with HCQ or placebo. The primary outcome measure will be change in total carotid plaque volume (TPV). Secondary outcome measures will be changes over time in total plaque surface area, maximal stenosis, and the type (fibrous, stable, or unstable), and stability of plaques. Specific Aim 2: will evaluate the extent to which HCQ can affect inflammation (SA2a), and vascular stiffness (SA2b) in CKD. We will examine the effects of HCQ and placebo at baseline, and at 6, 9, 12, and 18 months on the secondary outcome measures of high-sensitivity C-reactive protein (SA2a) and aortic pulse wave velocity (SA2b). Though the sample size and power calculations have been designed for the primary outcome (SA1), we will have adequate power to evaluate meaningful impacts of HCQ on the secondary outcomes in SA2. Specific Aim 3 will examine the effect of HCQ and placebo on the trends of hard cardiac and renal outcomes and drug safety. While not powered to detect the differences in the rates of these clinical events, trends in outcomes, drug safety, and tolerability are mandatory and will assist in the planning of the future, definitive RCT. If the results of this trial are positive with a favorable AE profile, it will provide critical preliminary data to justify and plan a definitive, multicenter RCT to examine the effects of HCQ on hard outcomes of CVD in CKD. Additionally, this study may provide insights into the importance of select inflammatory and vascular factors in CVD with wider future implications for those with CKD and perhaps the general population.

心血管疾病（CVD）是心血管疾病患者发病和死亡的最主要原因 慢性肾病（CKD）和终末期肾病（ESKD）。不幸的是，目前我们确实 没有有效的治疗方法来降低这些人群的高CVD死亡率。加速 动脉粥样硬化、炎症和血管僵硬度是导致 CKD CVD 的重要因素。 能够有效应对这些因素的干预措施可能会为疾病的管理带来显着的好处。 CKD 中的 CVD。羟氯喹（HCQ）是一种廉价且安全的抗炎药，已在 临床使用超过 40 年，甚至用于 CKD 和 ESKD 患者。近年来，在体外、体内、 基于人类队列的数据表明，HCQ 有益于 CVD 的多个参数，包括 炎症、内皮功能、代谢综合征、胰岛素敏感性和动脉粥样硬化。最近我们 通过我们的动物验证，HCQ确实具有显着的抗动脉粥样硬化和血管保护作用 在 CKD 环境中。我们进一步进行了一项小型、人性化的可行性研究，显示了 HCQ 在以下方面的潜力： 与 CKD 中 CVD 相关的参数。 下一步需要评估 HCQ 在 CKD 中 CVD 治疗中的作用。然而，在缺席的情况下 普遍认可的 CVD 替代物，需要进行一项概念验证临床研究来验证抗 HCQ 在 CKD 中的动脉粥样硬化和血管保护潜力。我们建议开展这样一项研究，将招募 90 名 随机对照试验 (RCT) 中的白蛋白尿、3b 期 CKD 受试者，分配比例为 1:1（HCQ：安慰剂）， 根据糖尿病状况分层，治疗持续时间为 18 个月。我们将研究 HCQ 对 动脉粥样硬化和心血管疾病的结构、功能和生化指标。 具体目标 (SA) 1 将评估 HCQ 与安慰剂相比减缓进展或逆转进展的能力 动脉粥样硬化。我们将通过非对比 MRI 评估颈动脉粥样硬化的进展 基线时以及使用 HCQ 或安慰剂治疗 9 个月和 18 个月后。主要结果指标将 颈动脉斑块总量（TPV）的变化。次要结果指标将随着时间的推移而变化 斑块总表面积、最大狭窄、斑块类型（纤维状、稳定或不稳定）以及斑块稳定性。 具体目标 2：将评估 HCQ 对炎症 (SA2a) 和血管僵硬度的影响程度 (SA2b) 在 CKD 中。我们将检查 HCQ 和安慰剂在基线以及 6、9、12 和 18 个月时的效果 高敏C反应蛋白（SA2a）和主动脉脉搏波的次要结果测量 速度（SA2b）。 尽管样本量和功效计算是针对主要结果 (SA1) 设计的，但我们 将有足够的权力来评估 HCQ 对 SA2 次要结果的有意义的影响。 具体目标 3 将检查 HCQ 和安慰剂对硬心脏和肾脏结局趋势的影响 和药品安全。虽然无法检测这些临床事件发生率的差异，但趋势 结果、药物安全性和耐受性是强制性的，并将有助于规划未来、明确的 随机对照试验。 如果该试验的结果是积极的且具有良好的 AE 特征，它将为以下方面提供关键的初步数据： 证明并计划一项明确的多中心随机对照试验，以检查 HCQ 对 CKD 中 CVD 硬结局的影响。 此外，这项研究可能有助于了解特定炎症和血管因素在疾病中的重要性。 CVD 对 CKD 患者甚至一般人群具有更广泛的未来影响。