Impact of Lp299v on Vascular Function in Patients With PASC
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 80
- 试验地点
- 2
- 主要终点
- Brachial Artery Flow Mediated Dilation (FMD%)
研究概览
简要总结
Emerging data show that SARS-CoV-2 infection causes gut microbiome changes strongly associated with Post-Acute Sequelae of SARS-CoV-2 (PASC). The investigators and others have established that an orally ingested probiotic (Lactobacillus plantarum 299v, Lp299v) reduces circulating levels of cell-free mitochondrial DNA (cf-mtDNA), decreases toll-like receptor 9 (TLR9) activation [and downstream interleukin (IL-6)], and improves micro- and macrovascular (brachial artery) endothelial dysfunction [as measured by flow-mediated dilation (FMD%)] in humans. Recently published data also report impaired brachial FMD% and increased vascular stiffness post-SARS-CoV-2 infection. Based on these data, the investigators hypothesize that supplementation with Lp299v will attenuate SARS-CoV-2 associated endothelial dysfunction by reducing cf-mtDNA, TLR9 activation, and inflammation.
详细描述
The intestinal immune system plays a critical role in systemic immunity, and its interaction with the systemic immune system plays a crucial role in determining the severity and outcomes of common pulmonary infections. SARS-CoV-2 infection alters the composition and metabolism of the gut microbiome. Greater losses of beneficial species in the human gut microbiome of SARS-CoV-2 patients are associated with severe disease and greater systemic inflammation. These pathological alterations are observed at least 6 months post-infection and are associated with greater residual systemic inflammation and PASC symptoms.
Six weeks of Lp299v supplementation in otherwise healthy smokers reduces circulating levels of the pro-inflammatory IL-6 and reduces monocyte adhesion to endothelial cells. IL-6 is elevated in patients with PASC and strongly correlates with TLR9 activation in disease states with high circulating cf-mtDNA levels. We published trial data showing once daily Lp299v supplementation (20 billion colony forming units/day) in men with coronary artery disease (CAD) improves endothelium-dependent vasodilation in the brachial artery and NO-dependent vasodilation of resistance arterioles from CAD patients. Further, preliminary data suggest Lp299v reduces circulating levels of cf-mtDNA (Fig. 2B). We also published data showing that 6 weeks of Lp299v has a significant anti-inflammatory effect on PBMC gene transcription, with gene ontology analyses indicating Lp299v supplementation inhibits TLR9 activation (z-score -3.48, P<0.0000000023). Combining the evidence that Lp299v reduces (1) circulating cf-mtDNA; (2) TLR9 activation; and (3) IL-6 levels while improving micro- and macrovascular endothelial function make Lp299v an excellent candidate to test as an intervention to improve vascular function in PASC patients.
Therefore, we will recruit subjects ages ≥18-89 who carry a clinical diagnosis of PASC and are within a window of 30-180-day post-acute symptom resolution into an 8-week, double-blind, randomized, placebo-controlled clinical trial of Lp299v supplementation. Measurements of micro- and macrovascular function, systemic inflammation, and stool microbiota composition will be made.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 89 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ages 18 to 89 years
- •30-180 days post-COVID-19 diagnosis
- •PASC diagnosed based on symptom report/expert physician judgement
排除标准
- •Antibiotics within four weeks of enrollment
- •History of chronic diseases (renal insufficiency, liver dysfunction, cancer requiring systemic treatment within 3 years of enrollment)
- •History of cognitive impairment/inability to follow study procedures
- •Short gut syndrome, inflammatory bowel disease, or an ileostomy.
- •Subjects currently taking Vitamin K antagonists such as coumadin or warfarin
- •Pregnant at the time of screening
- •Unstable coronary artery disease (new symptoms or event within 30 days of enrollment)
- •Daily alcohol use (may interfere with Lp299v's action)
研究组 & 干预措施
Lp299v
Subjects will consume 20 billion colony forming units of Lp299v (2 capsules) once daily for 8 weeks.
干预措施: Lactobacillus Plantarum 299v Freeze Dried Capsule (Other)
Heat-killed placebo control
Subjects will consume potato starch (2 capsules) once daily for 8 weeks.
干预措施: Freeze Dried Potato Starch Capsule (Other)
结局指标
主要结局
Brachial Artery Flow Mediated Dilation (FMD%)
时间窗: 8 weeks
This is a measurement of endothelial function in the brachial artery
次要结局
- Cell-Free Mitochondrial DNA (cf-mtDNA)(8 weeks)
- Carotid-Femoral Pulse Wave Velocity (cfPWV)(8 weeks)
- Stool microbiota beta diversity(8 weeks)
- Percentage of Laser Doppler Signal(8 weeks)
- Nitroglycerin-Mediated Vasodilation of the brachial artery (NMD)(8 weeks)
- Hyperemic Flow Velocity(8 weeks)
- interleukin-6(8 weeks)
- Stool microbiota alpha diversity(8 weeks)
- Brachial Artery Resting Diameter(8 weeks)
- Myeloid Cell Population phenotypes(8 weeks)
研究者
Michael E. Widlansky
Professor of Medicine and Pharmacology
Medical College of Wisconsin