Hydroxychloroquine for the Management of CVD in CKD

羟氯喹用于治疗 CKD 中的 CVD

• 批准号: 10578651
• 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 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578651
• 关键词: Acceleration; Adverse event; Affect; Agreement; Animal Model; Animals; Anti-Inflammatory Agents; Aorta; 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; Kidney Diseases; 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; Surface; Therapeutic; Time; Uremia; Veterans; 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; Acceleration; Adverse event; Affect; Agreement; Animal Model; Animals; Anti-Inflammatory Agents; Aorta; 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; Kidney Diseases; 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; Surface; Therapeutic; Time; Uremia; Veterans; 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）是患者发病率和死亡率的最显着原因 慢性肾脏疾病（CKD）和末期肾脏疾病（ESKD）。不幸的是目前，我们确实 没有有效的治疗方法可以降低这些人群中的高CVD死亡率。加速 动脉粥样硬化，炎症和血管僵硬是导致CKD中CVD的重要因素。 可以有效应对这些因素的干预措施可能会为管理带来重大好处 CKD中的CVD。羟氯喹（HCQ）是一种廉价且安全的抗炎药 即使在CKD和ESKD患者中，临床使用已有40多年。近来，多个体外，体内， 基于人类的数据表明，HCQ受益于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，HCQ确实具有明显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，人类的可行性研究，该研究显示了HCQ的潜力 与CKD中的CVD相关的参数。 下一步需要评估HCQ在CKD中处理CVD的作用。但是，在缺席的情况下 CVD的普遍商定的代替代物是一项概念证明的临床研究，以验证抗 HCQ在CKD中的动脉粥样硬化和血管保护潜力。我们提出了一项将注册90的研究 在1：1分配（HCQ：安慰剂）的随机对照试验（RCT）中，蛋白尿，3B阶段CKD受试者， 按照其糖尿病状况进行分层，并治疗18个月的时间。我们将检查HCQ对 动脉粥样硬化和CVD的结构，功能和生化测量。 特定目标（SA）1将评估与安慰剂相比，HCQ的能力，减慢进度或反向 动脉粥样硬化。我们将通过执行非对比度的MRI评估颈动脉粥样硬化的进展 在基线和使用HCQ或安慰剂治疗9和18个月后。主要结局措施将 变化总颈动脉斑块体积（TPV）。次要结果指标将随着时间的流逝而改变 总斑块表面积，最大狭窄以及斑块的类型（纤维，稳定或不稳定）和稳定性。 特定目标2：将评估HCQ可能影响炎症（SA2A）和血管刚度的程度 （SA2B）在CKD中。我们将在基线时检查HCQ和安慰剂的影响，以及6、9、12和18个月 关于高敏性C反应蛋白（SA2A）和主动脉脉冲波的次要结局测量 速度（SA2B）。 尽管已经为主要结果设计了样本量和功率计算（SA1），但我们 将具有足够的能力来评估HCQ对SA2次级结果的有意义影响。 特定目标3将检查HCQ和安慰剂对硬心和肾脏结果趋势的影响 和药物安全。虽然没有能力检测这些临床事件发生率的差异，但 结果，药物安全和耐受性是强制性的，将有助于计划未来，确定性 RCT。 如果该试验的结果呈正面呈正面AE概况，则将提供关键的初步数据 证明并计划确定的多中心RCT，以检查HCQ对CKD中CVD硬性结果的影响。 此外，这项研究可能会提供有关精选炎症和血管因素重要性的见解 CVD对CKD乃至一般人群的人具有更广泛的未来影响。