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2-HOBA Phase 2 Clinical Trial in Rheumatoid Arthritis

2-HOBA 类风湿关节炎 2 期临床试验

基本信息

批准号：
10364387
负责人：
Michelle Jane Ormseth
金额：
$ 18.15万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364387
关键词：
Adverse event Affect Amines Animal Model Animals Antioxidants Atherosclerosis Autoantibodies Autoimmune Diseases Autoimmunity Binding Blood Pressure Buckwheat C-reactive protein Cardiovascular Diseases Cell physiology Cells Clinical Research Clinical Trials DNA Dendritic Cells Disease Disease remission Dose Double-Blind Method Dropout Drug Kinetics Erythrocyte Sedimentation Rate Excess Mortality Future Hour Human Hypertension In Vitro Infiltration Inflammation Inflammatory Injury to Kidney Joints Lipid Peroxidation Malondialdehyde Measures Molecular Conformation Monitor Mus Outcome Oxidative Stress Pathway interactions Patients Persons Pharmaceutical Preparations Phase Phase II Clinical Trials Pilot Projects Placebos Plasma Population Prevention Production Property Proteins Pyridoxamine Randomized Reactive Oxygen Species Rheumatoid Arthritis Safety Signal Transduction Structure Systemic Lupus Erythematosus T-Cell Proliferation T-Lymphocyte Therapeutic Time Tissues Visit Vitamin E Work adduct aggressive therapy anti-dsDNA antibodies arm arthritis therapy atherosclerosis risk cardiovascular risk factor comorbidity compliance behavior covalent bond design effective therapy efficacy evaluation healthy volunteer immunogenic improved inflammatory marker lipid solubility mortality mouse model new therapeutic target novel novel strategies phase 2 study pill prevent secondary outcome treatment group

项目摘要

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease affecting 1% of the population. Aggressive treatment is a fundamental therapeutic strategy to improve disease-related outcomes and cardiovascular disease, which contributes to excess mortality in RA. Thus, therapeutics targeting novel pathways that treat RA and reduce cardiovascular risk are needed. A potential target is blocking the proinflammatory, immunogenic, and proatherogenic consequences of isolevuglandins (isoLGs). IsoLGs are highly reactive dicarbonyl products of oxidative stress that bind covalently to proteins causing conformational changes rendering them immunogenic and proinflammatory. Two decades of work at Vanderbilt led to the identification of 2-hydroxybenzylamine (2-HOBA) as a highly effective scavenger of reactive dicarbonyls such as isoLGs. Scavenging reactive dicarbonyls is preferable to using antioxidants because reactive oxygen species are necessary for normal cellular function. In animal models of autoimmunity, hypertension, and atherosclerosis 2-HOBA reduced inflammation, autoantibodies, blood pressure, and atherosclerosis, and in human phase 1 clinical studies in healthy volunteers 2-HOBA was well tolerated. We propose a phase 2 study to determine 2-HOBA’s tolerability, safety, and effect on isoLG- adducts, inflammation and blood pressure in RA patients. Twenty-eight subjects will be randomized to 750mg 2-HOBA or matching placebo three times a day for 12 weeks (14 per group). A visit at week 16 will assess for persisting effects after a 4-week washout. Aim 1 will compare tolerability and adverse events in active and placebo arms. Aim 2 will compare changes in cellular and plasma isoLG-adducts, markers of inflammation, DAS28 score, and 24-hour blood pressure in active and placebo arms. This pilot study will inform the feasibility and design of future studies to examine the efficacy of 2-HOBA in RA patients.

类风湿性关节炎 (RA) 是一种全身性炎症性自身免疫性疾病，影响 1% 的患者人口。积极治疗是改善疾病相关的基本治疗策略结局和心血管疾病，这导致 RA 死亡率过高。因此，治疗学需要针对治疗 RA 和降低心血管风险的新途径。一个潜在的目标是阻断异芥兰素的促炎、免疫原性和促动脉粥样硬化后果（isoLG）。 IsoLG 是氧化应激的高反应性二羰基产物，可与蛋白质共价结合引起构象变化，使它们具有免疫原性和促炎性。二十年来范德比尔特大学的工作导致 2-羟基苄胺 (2-HOBA) 被鉴定为一种高效的活性二羰基（例如 isoLG）的清除剂。清除活性二羰基优于使用抗氧化剂，因为活性氧是正常细胞功能所必需的。在动物模型中自身免疫、高血压和动脉粥样硬化 2-HOBA 减少炎症、自身抗体、血压和动脉粥样硬化，以及在健康志愿者中进行的人体 1 期临床研究 2-HOBA 耐受性良好。我们提出了一项 2 期研究，以确定 2-HOBA 的耐受性、安全性和对 isoLG- 的影响 RA 患者的加合物、炎症和血压。二十八名受试者将被随机分配到 750mg 2-HOBA 或匹配的安慰剂，每天 3 次，持续 12 周（每组 14 周）。第 16 周的访问将评估 4 周清除后的持续影响。目标 1 将比较耐受性和不良事件在活性组和安慰剂组中。目标 2 将比较细胞和血浆 isoLG 加合物的变化，这是活性组和安慰剂组的炎症、DAS28 评分和 24 小时血压。这项试点研究将告知未来研究的可行性和设计，以检查 2-HOBA 对 RA 患者的疗效。