Effects of Transvenous Vagus Nerve Stimulation on Immune Response: a pilot study

INTERVENTION: Product Name: Lipopolysaccharide Product Code: LPS Pharmaceutical Form: Powder and solvent for solution for injection INN or Proposed INN: lipopolysaccharide Current Sponsor code: LPS Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 1‐ CONDITION: Possible future indications: inflammatory conditions in general Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] PRIMARY OUTCOME: Main Objective: Determine the effect of transvenous vagus nerve stimulation (tVNS) on the innate immune response elicited by endotoxin administration in healthy volunteers up to 24 hours after stimulation. Primary end point(s): Plasma TNF‐a concentration after LPS administration (Are Under Curve); comparison of subjects treated with tVNS versus sham tVNS. Secondary Objective: • Determine effects of transvenous vagus nerve stimulation on autonomic nervous system activity up to 24 hours after stimulation ; • Determine effects of transvenous vagus nerve stimulation on ethylene and NO concentration in exhaled breath up to 24 hours after stimulation; • Determine tolerability of acute side effects of transvenous vagus nerve stimulation ; • Determine ease and safety of transvenous vagus nerve stimulation delivery; Timepoint(s) of evaluation of this end point: 0, 30, 60, 90, 120, 180, 240, 360, 480 minutes and 24 hours after endotoxin administration SECONDARY OUTCOME: Secondary end point(s): • Plasma concentrations of pro‐inflammatory and anti‐inflammatory cytokines (including TNF‐a, 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. ; • 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 ; • Endotoxemia‐related clinical symptoms, hemodynamic parameters, and temperature up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS. ; • Endotoxemia‐induced circulating leukocyte changes up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS. ; • Autonomic nervous system activity measured by heart rate variability up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS. ; • Ethylene and NO concentration in exhaled breath up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS. ; • Tolerability of acute side effects of tVNS ; • Ease of tVNS delivery ; Timepoint(s) of evaluation of this end point: at various time‐points or continuous between ‐60 minutes and 24 hours after LPS administration. INCLUSION CRITERIA: 1. Written informed consent to participate in this trial 2. Male subjects aged 18 to 35 years inclusive 3. Healthy as determined by medical history, physical examination, vital signs, 12 lead electrocardiogram, and clinical laboratory parameters Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range