Effects of Transvenous Vagus Nerve Stimulation on Immune Response: a Pilot Study

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of transvenous vagus nerve stimulation (tVNS) on the immune response. In the human endotoxemia model, intravenously administered endotoxin (lipopolysaccharide [LPS]) elicits a systemic immune response with release of pro-inflammatory cytokines, such as TNF α. This trial will determine if an anti-inflammatory effect can be produced by acute VNS using a minimally invasive delivery method.

Official Title
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Effects of Transvenous Vagus Nerve Stimulation on Immune Response: a Pilot Study

Conditions
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Inflammation

Intervention / Treatment
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* Device: Vagal Nerve Stimulation
* Device: Sham Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent to participate in this trial Male subjects aged 18 to 35 years inclusive Healthy as determined by medical history, physical examination, vital signs, 12 lead electrocardiogram, and clinical laboratory parameters Exclusion Criteria: Use of any medication(including herbal remedies and vitamin/mineral supplements) or recreational drugs within 7 days prior to profiling day Smoking Use of caffeine, or alcohol or within 1 day prior to profiling day Previous participation in a trial where LPS was administered Surgery or trauma with significant blood loss or blood donation within 3 months prior to profiling day Participation in another clinical trial within 3 months prior to profiling day. History, signs or symptoms of cardiovascular disease An implant that in the opinion of the investigator may make invasive procedures risky for the subject due to the increased risks associated with a possible infection. Subject has an implanted active cardiac device (ICD, IPG and/or CRT) Implanted active neurostimulation device Subject has internal jugular vein that cannot be accessed History of vaso-vagal collapse or of orthostatic hypotension History of atrial or ventricular arrhythmia Resting pulse rate ≤45 or ≥100 beats / min Hypertension (RR systolic >160 or RR diastolic >90) Hypotension (RR systolic <100 or RR diastolic <50) Conduction abnormalities on the ECG consisting of a 1st degree atrioventricular block or a complex bundle branch block Subject is diagnosed with epilepsy or history of seizures Renal impairment: plasma creatinine >120 µmol/L Liver function abnormality: alkaline phosphatase>230 U/L and/or ALT>90 U/L Coagulation abnormalities: APTT or PT > 1.5 times the reference range History of asthma Immuno-deficiency CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 2 weeks before profiling day Known or suspected of not being able to comply with the trial protocol Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vagal Nerve Stimulation<br>30 minutes of vagal nerve stimulation using a catheter in the IJV | Device: Vagal Nerve Stimulation<br>* 30 minutes of vagal nerve stimulation using a catheter in the IJV<br>|
| Sham Comparator: Sham stimulation<br>Catheter placed in the IJV without stimulation | Device: Sham Stimulation<br>* Catheter placed in the IJV without stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma TNF-α concentration | Plasma TNF-α concentration after LPS administration (Area Under Curve); comparison of subjects treated with tVNS versus sham tVNS. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of pro-inflammatory and anti-inflammatory cytokines | Plasma concentrations of pro-inflammatory and anti-inflammatory cytokines (including TNF-α, IL 6, IL 1RA, IL 10) up to 24 h after LPS injection to document the immune response up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS. | up to 24 h | 
| Leukocyte responses to ex vivo stimulation | Leukocyte responses to ex vivo stimulation with inflammatory stimuli and leukocyte phagocytosis capacity up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS | up to 24 hrs | 
| Endotoxemia-related clinical symptoms | Endotoxemia-related clinical symptoms, hemodynamic parameters, and temperature up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS. | up to 24 hrs | 
| Endotoxemia-induced circulating leukocyte changes | Endotoxemia-induced circulating leukocyte changes up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS. | up to 24 hrs | 
| Autonomic nervous system activity | Autonomic nervous system activity measured by heart rate variability up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS. | up to 24 hrs | 
| Tolerability of acute side effects of tVNS | Tolerability of acute side effects of tVNS. Subject feedback during VNS. | Acute 30 min stimulation | 
| Ease of tVNS delivery | Perception of delivery difficulty. | acute interoperative | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inflammation, vagus nerve stimulation, chronic heart failure, Systemic Inflammatory Response Syndrome, sepsis, auto-immune diseases