Transcutaneous Vagus Nerve Stimulation for the Treatment of Lupus

Study Overview
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Brief Summary
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This is a 3-month double blinded randomized controlled study of transcutaneous electrical vagus nerve stimulation (tVNS) compared to a sham stimulation for the treatment of patients with active systemic lupus erythematosus (SLE).

Detailed Description
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Patients with SLE and active, non-organ-threatening disease are eligible to participate in this prospective randomized double blind trial of active or sham transcutaneous electrical vagus nerve stimulation (tVNS). Active tNVS is performed by the use of a transcutaneous electrical nerve stimulation (TENS) device with electrodes attached to an area of the external ear innervated by the auricular branch of the vagus nerve. The same protocol is followed in the sham tVNS arm, but the pads are placed on an area of the external ear that is devoid of vagus innervation.TENS is applied for 60 to 120 minutes daily as tolerated and participants keep a detailed log of their daily TENS sessions. Patients return to clinic at weeks 4, 8 and 12 for study related assessments.

Official Title
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Transcutaneous Vagus Nerve Stimulation for the Treatment of Systemic Lupus Erythematosus

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Device: TENS for vagus stimulation
* Device: TENS for sham stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with SLE age 18-70 meeting the American College of Rheumatology Classification Criteria. Patients need to meet a minimum of 4 out of 11 criteria simultaneously or serially on two separate occasions. Positive antinuclear antibody or anti-dsDNA within one year of screening Non-serological SLEDAI ≥4 or ≥1 BILAG B or A and presence of inflammatory arthritis (defined by at least 3 swollen and 3 tender joints) at screening Patients may receive on one or more of the following immune suppressive therapies: hydroxychloroquine, quinacrine, methotrexate, azathioprine, mycophenolate mofetil, tacrolimus, sirolimus, belimumab, abatacept. Immune suppressive medications should have been administered at stable doses for ≥30 days prior to baseline. Patients may also be on prednisone up to 10mg daily or equivalent steroid treatment at the baseline visit. Exclusion Criteria: Acute lupus nephritis defined as class II,III, IV or V nephritis diagnosed within 6 months or prot/creat > 1.5 gm/gm due to active lupus or in process of receiving induction therapy for nephritis Active CNS lupus affecting mental status Any other organ threatening or life threatening manifestation of SLE as well as those, who, in the opinion of the investigator, have severe multi-organ or refractory lupus Rituximab treatment within 6 months prior to screening and/or without return of B cells to baseline levels Treatment with cyclophosphamide within a month prior to screening Treatment with any investigational drug within 3 months or 5 half-lives whichever is longer Recurrent vaso-vagal syncopal episodes Unilateral or bilateral vagotomy Presence of any evidence of vagus nerve pathology or injury Heart failure (NYHA class III or IV) Known atherosclerotic disease, including severe carotid artery disease, uncontrolled hypertension, uncontrolled diabetes, and history of myocardial infarction (MI), cardiomyopathy or stroke within the past year. Clinically stable patients with coronary artery disease, but no recent MI (within the past year) and no current symptoms of angina are not however excluded. Valvular and other structural heart disease that is evident by transthoracic echocardiogram and is associated with heart failure (NYHA class III or IV) Prolonged QT interval or abnormal baseline ECG - sick sinus syndrome, Mobitz type 2 second or third degree heart block, atrial fibrillation, atrial flutter, recent history of ventricular tachycardia or ventricular fibrillation or clinically significant premature ventricular contraction Individuals currently implanted with an electrical and/or neurostimulator device, such as cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain stimulator, spinal stimulator, bone growth stimulator, or cochlear implant Known respiratory disease that has decreased any pulmonary function test more than 25% below expected values or has resulted in hospitalization within the past year All diagnosed syndromes affecting the central nervous system (CNS) or autonomic nervous system Major psychiatric disorders including evidence of major depressive disorder (DSM-5 diagnostic criteria) that is not currently controlled by medications Hemoglobin below 9.0 gm/dL (by the most recent CBC) Pregnancy or breast feeding Inability or unwillingness to understand and/or sign informed consent Any other medical condition, whether or not related to lupus, which, in the opinion of the investigator, would render the patient inappropriate or too unstable to complete the study protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TENS for vagus stimulation<br>A transcutaneous electrical nerve stimulation (TENS) unit is applied to an area of the external ear that is innervated by the auricular branch of the vagus nerve. | Device: TENS for vagus stimulation<br>* TENS electrodes are applied on an area of the external ear innervated by the auricular branch of the vagus nerve.<br>|
| Sham Comparator: TENS for sham stimulation<br>A TENS unit is applied to an area of the external ear that is devoid of vagus innervation. | Device: TENS for sham stimulation<br>* TENS electrodes are applied on an area of the external ear devoid of vagus innervation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA) | Achieving a BICLA response requires to meet all of the following parameters: All British Isles Lupus Assessment Group (BILAG) A scores improving to B/C/D and all BILAG level B scores improving to C/D No single new BILAG A & not >1 new BILAG B scores, no worsening of the baseline Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) total score AND no worsening in the Physician Global Assessment (PGA) (<10% worsening from baseline) No initiation of non-protocol treatments or premature study discontinuation The range of values for the above instruments are listed below, with higher scores indicating more active disease: BILAG: 0 to 96 SLEDAI: 0 to 105 PGA: 0-3 | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the Systemic Lupus Erythematosus Responder Index (SRI-4) | SRI requires meeting all of the following parameters: ≥4-point reduction from baseline in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score No single new British Isles Lupus Assessment Group (BILAG) A score & not >1 new BILAG B scores AND no worsening in the Physician Global Assessment (PGA) (<10% worsening from baseline) No initiation of non-protocol treatments or premature study discontinuation The range of values for the above instruments are listed below, with higher scores indicating more active disease: BILAG: 0 to 96 SLEDAI: 0 to 108 PGA: 0-3 | 12 weeks | 
| Percentage of Participants on Active vs Sham tVNS With Improvement in Heart Rate Variability (HRV) | HRV is measured by time domain (RMSSD and pNN50) and frequency domain [high frequency (HF), low to high frequency (LF/HF) ratio] parameters. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vagus nerve stimulation, systemic lupus erythematosus