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：
10610318
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/10610318
关键词：
Adverse event Affect Amines Animal Model Animals Antioxidants Aorta 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 Reaction Reactive Oxygen Species Rheumatoid Arthritis Safety Signal Transduction Structure Systemic Lupus Erythematosus T-Cell Proliferation T-Lymphocyte Therapeutic 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 joint inflammation 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.

类风湿关节炎（RA）是一种全身性炎症自身免疫性疾病，影响1％人口。积极的治疗是一种基本的治疗策略，可改善与疾病有关结局和心血管疾病，导致RA死亡率过多。那，治疗需要针对治疗RA并减少心血管风险的新型途径。一个潜在的目标是阻止异甲曲蛋白的促炎，免疫原性和促进性的后果（隔离）。隔离是高度反应性的氧化应激产物，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。二十年的范德比尔特的工作导致鉴定2-羟基苯胺（2-HOBA）是一种高效清除反应性双龙酮，例如隔离。清除反应性dicarbonyls比使用更可取抗氧化剂是因为活性氧对于正常细胞功能是必需的。在动物模型中自身免疫性，高血压和动脉粥样硬化2-HOBA减少注射，自身抗体，血压和动脉粥样硬化，以及在健康志愿者2-HOBA的人类1期临床研究中耐受性良好。我们提出了一项第二阶段研究，以确定2-HOBA的耐受性，安全性和对隔离的影响 RA患者的加合性，炎症和血压。二十八名受试者将被随机分配给 750mg 2-HOBA或每天三次匹配安慰剂12周（每组14）。第16周的访问将 4周冲洗后评估持续效果。 AIM 1将比较耐受性和不利事件在主动和安慰剂的手臂上。 AIM 2将比较细胞和等离子体隔离的变化，活跃和安慰剂组的炎症，DAS28评分以及24小时的血压。这项试验研究将告知未来研究的可行性和设计，以检查2-HOBA在RA患者中的效率。