Scavenging IsoLGs in Autoimmune Disease: a Proof-of-concept Clinical Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 42
- 试验地点
- 2
- 主要终点
- 24-hour systolic blood pressure
研究概览
简要总结
This is a phase II randomized, placebo-controlled, double-blind, cross-over study to determine the effect of isolevuglandin (IsoLG) scavenging by 2-HOBA on blood pressure and immune activation in patients with SLE. 42 patients with stable SLE will be randomized to treatment sequence to receive placebo or 500mg 2-HOBA three times a day for 8 weeks followed by a 4 week washout and then 8 weeks of the other agent.
Primary outcome measures include change in 24-hour blood pressure and NETosis. This study will provide mechanistic information on the role of IsoLGs in autoimmune disease-associated hypertension and immune activation.
详细描述
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a markedly increased prevalence of not only hypertension but also resistant hypertension. Hypertension, along with other factors, leads to a 2 to 3-fold increase in risk of cardiovascular disease in SLE. Other than glucocorticoids and immunosuppression, there are few therapeutic options for patients with SLE and none that are known to have a beneficial effect on hypertension and cardiovascular disease; in fact, glucocorticoids have substantial deleterious effects. The increased prevalence of hypertension and its greater severity in SLE patients are unexplained; however, work from our group and others increasingly implicates activation of the immune system in the pathogenesis of hypertension. Moreover, our data suggest that downstream products of oxidative stress, specifically isolevuglandins (IsoLGs), drive immune activation and hypertension.
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 SLE, hypertension, and atherosclerosis 2-HOBA reduced inflammation, neutrophil extracellular traps (NETosis), blood pressure, and atherosclerosis, and in human phase I clinical studies with healthy volunteers it was well tolerated.
This is a mechanistic, proof-of-concept phase II study with a randomized, placebo-controlled, double-blind, cross-over design to determine the effect of IsoLG scavenging by 2-HOBA on blood pressure and immune activation in patients with SLE. 42 patients with stable SLE will be randomized to treatment sequence to receive placebo or 500mg 2-HOBA three times a day for 8 weeks followed by a 4 week washout and then 8 weeks of the other agent. Comparing 2-HOBA and placebo arms, primary outcomes include change in 24-hour blood pressure and immune activation measured by NETosis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Written informed consent
- •Age ≥18 years
- •Female (biological)
- •Meeting the 2019 European League Against Rheumatism/ American College of Rheumatology classification criteria for SLE32
- •No change in immunosuppressants ≥3 months
- •Stable prednisone (or equivalent) dose ≤ 20mg/ day for ≥ 1 month
- •Elevated blood pressure defined as >120 and < or = 160 mmHg systolic or >80 and < or = 110 mmHg diastolic blood pressure at screening visit
- •No change in anti-hypertensive dose ≥2 weeks
- •Willingness to stop NSAIDs for ≥2 weeks before and throughout the study
- •If of childbearing potential, willingness to use effective birth control throughout the study and 4 weeks after completion of the study (examples: condom, diaphragm, oral contraceptive pill, intrauterine device)
排除标准
- •Pregnant or breastfeeding
- •Male (biological)
- •Active cancer except for non-melanoma skin cancer
- •Prior diagnosis of liver cirrhosis or the following abnormal liver function studies: AST or ALT >1.5x the upper limit of normal or total bilirubin ≥1.5 mg/dl
- •Active infection requiring medical intervention
- •Major surgery in ≤ 3 months
- •Aspirin allergy
- •Use of MAO-I
- •Estimated creatinine clearance <30 ml/min
- •Known atrial fibrillation
- •Severe comorbid condition
研究组 & 干预措施
Placebo First
Placebo for first 8 weeks, then washout for 4 weeks, and then 2-HOBA acetate for 8 weeks
干预措施: 2-HOBA acetate (2-Hydroxybenzlamine acetate) (Drug)
Placebo First
Placebo for first 8 weeks, then washout for 4 weeks, and then 2-HOBA acetate for 8 weeks
干预措施: Placebo (Drug)
2-HOBA First
2-HOBA acetate for first 8 weeks, then washout for 4 weeks, and then placebo for 8 weeks
干预措施: 2-HOBA acetate (2-Hydroxybenzlamine acetate) (Drug)
2-HOBA First
2-HOBA acetate for first 8 weeks, then washout for 4 weeks, and then placebo for 8 weeks
干预措施: Placebo (Drug)
结局指标
主要结局
24-hour systolic blood pressure
时间窗: Measured at the beginning and end of each phase at weeks 0, 4, 8, and 12.
Investigators will measure change in 24-hour systolic blood pressure
NETosis
时间窗: Measured at beginning and end of each phase at weeks 0, 4, 8, and 12.
Investigators will measure change in NETosis by ELISA assessing circulating NET concentration
次要结局
未报告次要终点
研究者
Michelle Ormseth
Associate Professor
Vanderbilt University Medical Center