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

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.

Study Overview

• Status: Completed
• Conditions: Inflammation
• Intervention / Treatment: Device: Vagal Nerve Stimulation; Device: Sham Stimulation

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 9101
    • Radboud University Nijmegen Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Medtronic Cardiac Rhythm and Heart Failure
• Collaborators: Radboud University Medical Center
• Investigators: Principal Investigator: Peter Pickkers, MD, Radboud University Medical Center

Publications and helpful links

General Publications

• Kox M, van Eijk LT, Verhaak T, Frenzel T, Kiers HD, Gerretsen J, van der Hoeven JG, Kornet L, Scheiner A, Pickkers P. Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study. Arthritis Res Ther. 2015 Jun 7;17(1):150. doi: 10.1186/s13075-015-0667-5.

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: September 12, 2013
• First Submitted That Met QC Criteria: September 12, 2013
• First Posted (Estimate): September 17, 2013

Study Record Updates

• Last Update Posted (Estimate): October 31, 2013
• Last Update Submitted That Met QC Criteria: October 29, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: inflammation; sepsis; Systemic Inflammatory Response Syndrome; vagus nerve stimulation; chronic heart failure; auto-immune diseases
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation
• Other Study ID Numbers: NoSIRS Study; 2012-005687-97 (EudraCT Number)