Clinical trial NCT01944228: Effects of Transvenous Vagus Nerve Stimulation on Immune Response: a Pilot Study
Official title: Effects of Transvenous Vagus Nerve Stimulation on Immune Response: a Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Inflammation
Keywords: inflammation
vagus nerve stimulation
chronic heart failure
Systemic Inflammatory Response Syndrome
sepsis
auto-immune diseases
Lead sponsor: Medtronic Cardiac Rhythm and Heart Failure
Sponsor class: INDUSTRY
Collaborators: name: Radboud University Medical Center
First posted: 2013-09-17
Enrollment: 22
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Plasma TNF-α concentration
timeFrame: 24 hours
Secondary outcomes:
measure: Plasma concentrations of pro-inflammatory and anti-inflammatory cytokines
timeFrame: up to 24 h
measure: Leukocyte responses to ex vivo stimulation
timeFrame: up to 24 hrs
measure: Endotoxemia-related clinical symptoms
timeFrame: up to 24 hrs
measure: Endotoxemia-induced circulating leukocyte changes
timeFrame: up to 24 hrs
measure: Autonomic nervous system activity
timeFrame: up to 24 hrs
measure: Tolerability of acute side effects of tVNS
timeFrame: Acute 30 min stimulation
measure: Ease of tVNS delivery
timeFrame: acute interoperative
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
Study officials:
affiliation: Radboud University Medical Center
name: Peter Pickkers, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.