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

Primary Purpose

Inflammation

Status

Completed

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

Vagal Nerve Stimulation

Sham Stimulation

About this trial

This is an interventional basic science trial for Inflammation focused on measuring inflammation, vagus nerve stimulation, chronic heart failure, Systemic Inflammatory Response Syndrome, sepsis, auto-immune diseases

Eligibility Criteria

18 Years - 35 Years (Adult)MaleAccepts Healthy Volunteers

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.

Sites / Locations

Radboud University Nijmegen Medical Centre

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Vagal Nerve Stimulation

Sham stimulation

Arm Description

30 minutes of vagal nerve stimulation using a catheter in the IJV

Catheter placed in the IJV without stimulation

Outcomes

Primary Outcome Measures

Plasma TNF-α concentration

Plasma TNF-α concentration after LPS administration (Area Under Curve); comparison of subjects treated with tVNS versus sham tVNS.

Secondary Outcome Measures

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.

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

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.

Endotoxemia-induced circulating leukocyte changes

Endotoxemia-induced circulating leukocyte changes up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS.

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.

Tolerability of acute side effects of tVNS

Tolerability of acute side effects of tVNS. Subject feedback during VNS.

Ease of tVNS delivery

Perception of delivery difficulty.

Full Information

NCT ID

NCT01944228

First Posted

September 12, 2013

Last Updated

October 29, 2013

Sponsor

Medtronic Cardiac Rhythm and Heart Failure

Collaborators

Radboud University Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT01944228

Brief Title

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

Acronym

NoSIRS

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2013

Overall Recruitment Status

Completed

Study Start Date

August 2013 (undefined)

Primary Completion Date

October 2013 (Actual)

Study Completion Date

October 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Medtronic Cardiac Rhythm and Heart Failure

Collaborators

Radboud University Medical Center

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Inflammation

Keywords

inflammation, vagus nerve stimulation, chronic heart failure, Systemic Inflammatory Response Syndrome, sepsis, auto-immune diseases

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

22 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Vagal Nerve Stimulation

Arm Type

Experimental

Arm Description

30 minutes of vagal nerve stimulation using a catheter in the IJV

Arm Title

Sham stimulation

Arm Type

Sham Comparator

Arm Description

Catheter placed in the IJV without stimulation

Intervention Type

Device

Intervention Name(s)

Vagal Nerve Stimulation

Intervention Description

30 minutes of vagal nerve stimulation using a catheter in the IJV

Intervention Type

Device

Intervention Name(s)

Sham Stimulation

Intervention Description

Catheter placed in the IJV without stimulation

Primary Outcome Measure Information:

Title

Plasma TNF-α concentration

Description

Plasma TNF-α concentration after LPS administration (Area Under Curve); comparison of subjects treated with tVNS versus sham tVNS.

Time Frame

24 hours

Secondary Outcome Measure Information:

Title

Plasma concentrations of pro-inflammatory and anti-inflammatory cytokines

Description

Time Frame

up to 24 h

Title

Leukocyte responses to ex vivo stimulation

Description

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

Time Frame

up to 24 hrs

Title

Endotoxemia-related clinical symptoms

Description

Endotoxemia-related clinical symptoms, hemodynamic parameters, and temperature up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS.

Time Frame

up to 24 hrs

Title

Endotoxemia-induced circulating leukocyte changes

Description

Endotoxemia-induced circulating leukocyte changes up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS.

Time Frame

up to 24 hrs

Title

Autonomic nervous system activity

Description

Autonomic nervous system activity measured by heart rate variability up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS.

Time Frame

up to 24 hrs

Title

Tolerability of acute side effects of tVNS

Description

Tolerability of acute side effects of tVNS. Subject feedback during VNS.

Time Frame

Acute 30 min stimulation

Title

Ease of tVNS delivery

Description

Perception of delivery difficulty.

Time Frame

acute interoperative

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

35 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Peter Pickkers, MD

Organizational Affiliation

Radboud University Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Radboud University Nijmegen Medical Centre

City

Nijmegen

ZIP/Postal Code

9101

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

26049730

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.

Results Reference

derived

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

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