Transcutaneous Vagus Nerve Stimulation for the Treatment of Lupus

Phase 2

Terminated

Conditions: Systemic Lupus Erythematosus

Interventions: Device: TENS for sham stimulation
Device: TENS for vagus stimulation

Registration Number: NCT02917265

Lead Sponsor: Aikaterini Thanou

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 7

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TENS for sham stimulation	TENS for sham stimulation	A TENS unit is applied to an area of the external ear that is devoid of vagus innervation.
TENS for vagus stimulation	TENS for vagus stimulation	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the BILAG-based Combined Lupus Assessment (BICLA)	12 weeks	Achieving a BICLA response requires to meet all of the following parameters: 1. All British Isles Lupus Assessment Group (BILAG) A scores improving to B/C/D and all BILAG level B scores improving to C/D 2. 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) 3. 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

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants on Active vs Sham tVNS With Improvement in SLE Disease Activity by the Systemic Lupus Erythematosus Responder Index (SRI-4)	12 weeks	SRI requires meeting all of the following parameters: 1. ≥4-point reduction from baseline in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score 2. 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) 3. 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
Percentage of Participants on Active vs Sham tVNS With Improvement in Heart Rate Variability (HRV)	12 weeks	HRV is measured by time domain (RMSSD and pNN50) and frequency domain \[high frequency (HF), low to high frequency (LF/HF) ratio\] parameters.