Mechanism of Isolevuglandin-Protein Adduct Formation in Persistent Immune Activation in Long COVID POTS
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 50
- 主要终点
- Effect IsoLG-adducts (2-HOBA) measured by levels of monocyte/T cell doublets in LCPOTS.
研究概览
简要总结
Long COVID is defined by a range of symptoms affecting multiple organs that persist for more than three months following an acute SARS-CoV-2 infection. Approximately 7% of individuals who recover from SARS-Cov-2 infection develop Long COVID.
Long COVID Postural Orthostatic Tachycardia Syndrome (LCPOTS) symptoms include fatigue, exercise intolerance, orthostatic intolerance, syncope, and heightened orthostatic tachycardia.
Research has found that decreased parasympathetic activity in LCPOTS increases the production of highly immunogenic neoantigens Isolevuglandins (IsoLG-adducts). IsoLG-adducts induce formation of circulating monocyte/T cell complexes(doublets) leading to the persistent and unresolved immune response that continues after the initial infection.
The purpose of the this research, is to study the effects of 2-hydroxybenzylamine (2-HOBA), an Iso-LG-adduct scavenger, its effects in immune markers and compare it with Placebo
详细描述
Background:
Decreased parasympathetic activity is present in LCPOTS; this system is an important modulator of NAPDH oxidase activity because the activation of NADPH oxidase in monocytes promotes superoxide (reactive oxygen species -ROS) production.Oxidative stress occurs when ROS are generated in excess of normal antioxidants. Oxidative stress occurs when reactive oxygen species (ROS) are generated in excess of normal antioxidantsOxidative stress occurs when reactive oxygen species (ROS) are generated in excess of normal antioxidants that can cause harm by having adverse effects on T cell function. Targeting downstream damaging effects of ROS is an attractive alternative.
Rationale and Specific Aims
Reduced parasympathetic activity increases the production of highly immunogenic neoantigens, Isolevuglandins (IsoLG-adducts), through heightened activation of NADPH oxidase. Previous findings demonstrated that the cholinergic enhancer galantamine, reduces NADPH oxidase activation and that vagal stimulation reduces IsoLG-adducts in immune cells of LCPOTs patients.
Immune activation in response to viral or likely self-antigen presentation can induce formation of circulating monocyte/T cell complexes(doublets).The presence of these doublets provides powerful insights into the persistent and unresolved immune response that continues after the initial infection. The preliminary data show that: 1) LCPOTS subjects have markedly increased circulating doublets compared to controls; 2) T cells in these doublets produce higher levels of inflammatory cytokines IL-17A and IFN-ɣ than singlet T cells; and 3) inflammatory cytokines positively associate with the severity of orthostatic tachycardia in LCPOTS.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
A licensed MTI BioTech (MTI) to develop 2-HOBA. MTI will provide 2-HOBA and matching placebo capsules for the study . Capsules will be shipped to the Vanderbilt Investigational Drug Services (IDS) for use in this trial. The IDS will be responsible for storage, and labeling of 2-HOBA and matching placebo, and for maintaining accurate drug storage and dispensing logs.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All participants should meet diagnostic criteria for Long COVID and POTS and as outlined below:
- •Long COVID (LC) is defined by a range of symptoms affecting multiple organs that persist for more than three months following an acute SARS-CoV-2 infection.
- •POTS: the presence of chronic symptoms lasting more than 3 months, along with orthostatic tachycardia (a HR increase over 30 bpm upon standing or exceeding 120 bpm without orthostatic hypotension) within 10 minutes upon standing or 75-degree head up tilt.
- •For patients aged 18 and 21, an increase of more than 40 bpm or a standing HR over 130 bpm will be required for inclusion in the study.
- •2 Patients need confirmation of POTS diagnosis based on orthostatic vital signs obtained prior to enrollment in the study.
- •SARS-CoV-2 infection 3 or more months prior identified by the follow signs:
- •A. Meets the clinical OR epidemiological criteria.
- •Clinical criteria: Acute onset of fever AND cough (influenza-like illness) OR Acute onset of ANY THREE OR MORE of the following signs or symptoms: fever, cough, general, weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, nausea, diarrhea, anorexia.
- •Epidemiological criteria: Contact of a probable or confirmed case or linked to a COVID-19 cluster; or B. Presents with acute respiratory infection with history of fever or measured fever of ≥ 38°C; and cough; with onset within the last 10 days; and who requires hospitalization); or C. Presents with no clinical signs or symptoms, NOR meeting epidemiologic criteria with a positive professional use or self-test SARS-CoV-2 antigen-Rapid Diagnostic Test.
- •D. A person with a positive nucleic acid amplification test, regardless of clinical criteria OR epidemiological criteria; or E. Meeting clinical criteria AND/OR epidemiological criteria (See A). With a positive professional use or self-test, SARS-CoV-2 Antigen-Rapid Diagnostic Test.
- •F. Documented by health care provider in clinical note or encounter.
排除标准
- •Known active acute SARS-Cov-2 infection (4 weeks from onset)
- •Moderate or severe immunocompromised patients,
- •Known history of cardiovascular disease (atrioventricular block (AV block), myocardial infarction, angina, heart failure, pacemaker, stroke, transient ischemic attack within 6 months before enrollment),
- •Uncontrolled hypertension (BP>140/90 despite appropriate treatment);
- •Type 1 or type 2 diabetes mellitus;
- •Impaired hepatic function (AST or ALT greater than 1.5x the upper limit of normal or with total bilirubin ≥1.5mg/dl),
- •Impaired renal function test (eGFR<60 mL/min/1.73m2),
- •Anemia (hemoglobin <10 g/dl),
- •Pregnant or breastfeeding women,
- •Known history of autoimmune disease, steroid use or other immunotherapies,
- •Inability to provide informed consent.
- •We will also exclude individuals with known allergy sensitivity to components of the study medication, known contraindication to the study interventions, use of central acetylcholinesterase inhibitors (e.g., pyridostigmine, donezepil), aspirin allergy because salicylic acid is a metabolite of 2-HOBA; use of monoamine oxidase inhibitors (MAO-I) because of some inhibition of MAO-A is present in the anticipated therapeutic range of 2-HOBA.
研究组 & 干预措施
Levels of circulating monocyte/ T cell doublets, and inflammatory cytokines in 2 HoBA Vs Placebo
to test the effect of 28-day treatment with Iso-LG-adduct scavenger, 2-hydroxybenzylamine (2-HOBA) versus placebo on circulating monocyte/ T cell doublets (CD14+CD3+) , and inflammatory cytokines
干预措施: To Measure levels of circulating monocyte/ T cell doublets at Baseline (Drug)
Levels of circulating monocyte/ T cell doublets, and inflammatory cytokines in 2 HoBA Vs Placebo
to test the effect of 28-day treatment with Iso-LG-adduct scavenger, 2-hydroxybenzylamine (2-HOBA) versus placebo on circulating monocyte/ T cell doublets (CD14+CD3+) , and inflammatory cytokines
干预措施: To measure levels of circulating monocyte/ T cell doublets after 28 days of 2 HOBA treatment (Drug)
Levels of circulating monocyte/ T cell doublets, and inflammatory cytokines in 2 HoBA Vs Placebo
to test the effect of 28-day treatment with Iso-LG-adduct scavenger, 2-hydroxybenzylamine (2-HOBA) versus placebo on circulating monocyte/ T cell doublets (CD14+CD3+) , and inflammatory cytokines
干预措施: To measure levels of circulating monocyte/ T cell doublets after 28 days of Placebo treatment (Drug)
Effect of 2HOBA on Splanchnic venous capacitance and compare with placebo group on POTS patients
To test the hypothesis that IsoLG-adducts directly contribute to splanchnic vasodilation, by assessing changes in splanchnic venous capacitance with 2-HOBA treatment at head up Tilt
干预措施: To Measure Splanchnic venous capacitance after 28 days of Treatment with 2HOBA (Diagnostic Test)
Effect of 2HOBA on Splanchnic venous capacitance and compare with placebo group on POTS patients
To test the hypothesis that IsoLG-adducts directly contribute to splanchnic vasodilation, by assessing changes in splanchnic venous capacitance with 2-HOBA treatment at head up Tilt
干预措施: To Measure Splanchnic venous capacitance after 28 days of Treatment with Placebo (Diagnostic Test)
Effect of 2HOBA on Orthostatic Tachycardia compare with placebo group during 30 minutes head up tilt
To test that IsoLG-adducts directly effect Orthostatic tachycardia in LCPOTS, during 30-minute head-up tilt.
干预措施: To Measure Orthostatic Tachycardia after 28 days of Treatment with 2HOBA (Diagnostic Test)
Effect of 2HOBA on Orthostatic Tachycardia compare with placebo group during 30 minutes head up tilt
To test that IsoLG-adducts directly effect Orthostatic tachycardia in LCPOTS, during 30-minute head-up tilt.
干预措施: To Measure Orthostatic Tachycardia after 28 days of Treatment with Placebo (Diagnostic Test)
结局指标
主要结局
Effect IsoLG-adducts (2-HOBA) measured by levels of monocyte/T cell doublets in LCPOTS.
时间窗: Baseline (Day 0) to after 28 days of treatment
The effect of 28-day treatment with Iso-LG-adduct scavenger, 2-hydroxybenzylamine (2-HOBA) versus placebo on circulating monocyte/ T cell doublets, and inflammatory cytokines and compare it to the placebo
Changes in Splanchnic venous capacitance before and after 28 days of treatment
时间窗: Day 0- Day 28 days
Changes in Splanchnic venous capacitance at 30 mins Head up tilt, before and after 28 days of treatment and compare it with 2-HOBA group with placebo group
次要结局
- Measure the effects of 2- HOBA on Orthostatic Tachycardia at HUT(Baseline (Day0) to after 28 days of study medication)
研究者
Cyndya Shibao, MD
Professor
Vanderbilt University Medical Center