Clinical trial NCT05227170: Impact of Lp299v on Vascular Function in Patients With PASC
Official title: Impact of Lp299v on Vascular Function in Patients With PASC
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: COVID-19
Keywords: endothelial function
PASC
COVID-19
inflammation
microbiome
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
First posted: 2022-02-07
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Ages 18 to 89 years
* 30-180 days post-COVID-19 diagnosis
* PASC diagnosed based on symptom report/expert physician judgement

Exclusion Criteria:

* 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)

Primary outcomes:
measure: Brachial Artery Flow Mediated Dilation (FMD%)
timeFrame: 8 weeks
Secondary outcomes:
measure: Nitroglycerin-Mediated Vasodilation of the brachial artery (NMD)
timeFrame: 8 weeks
measure: Hyperemic Flow Velocity
timeFrame: 8 weeks
measure: Carotid-Femoral Pulse Wave Velocity (cfPWV)
timeFrame: 8 weeks
measure: Percentage of Laser Doppler Signal
timeFrame: 8 weeks
measure: interleukin-6
timeFrame: 8 weeks
measure: Stool microbiota alpha diversity
timeFrame: 8 weeks
measure: Stool microbiota beta diversity
timeFrame: 8 weeks
measure: Cell-Free Mitochondrial DNA (cf-mtDNA)
timeFrame: 8 weeks
measure: Brachial Artery Resting Diameter
timeFrame: 8 weeks
measure: Myeloid Cell Population phenotypes
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Medical College of Wisconsin
name: Michael E Widlansky, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: