Efficacy of Non-invasive Vagus Nerve Stimulation for Axial Spondyloarthritis Resistant to Biotherapies

Study Overview
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Brief Summary
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The primary objective of the study is to study the change in SpA disease activity, according to ASAS20 definition (Anderson et al., 2001), after 8 weeks of VNS treatment versus placebo non-specific stimulation (control group). The secondary objectives of the Clinical Investigation are to show differences in disease evolution between the active and placebo periods of 8 weeks treatment with active VNS versus placebo VNS of the following items: Change in disease activity according to ASAS40 criteria Obtaining a partial remission according to the ASAS definition Change in BASFI Change in C-reactive protein (CRP)serum level and erythrocytes sedimentation rate (ESR), Change in ASDAS_CRP and ASDAS_ESR Difference in levels of circulating cytokines, IL-6, IL-23, IL-17, IL-33 and of matrix metallopeptidases (MMP3-8-9). Change in quality of life : assessment according to the following indexes: SF-36, AS Quality of Life (ASQOL) Change in Health Index of patient with SpA (ASAS HI) and of the Productivity at Work Index (WPI) Change in fatigue (BASDAI 1st question) and global pain Change in Anxiety and Depression Assessment (HAD) Change in BASMI Change in non-steroidal anti-inflammatory drugs (NSAID) intake score.

Detailed Description
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This multi-center study will be conducted in rheumatology departments of 14 public hospitals in France. The study is part of the SMART-VNS (TM) project: a Structured Multidisciplinary Program for Advanced Research on the Therapeutic effects of Vagus Nerve Stimulation in inflammatory, infectious, neurological and painful diseases. After informed consent, patients will be included in the Clinical Investigation by rheumatologists during routine consultations. Included patients will be randomised in two groups differing by the sequence in which the treatments are to be administered: Group A: VNS active for 8 weeks, then VNS placebo for 8 weeks; and Group B: VNS placebo for 8 weeks then VNS active for 8 weeks. In order to maintain the blind, investigators administering the stimulation will be different from those evaluating the patients, and the latter will be blinded to the treatment administered. A transcutaneous vagus nerve stimulator Tens Eco Plus SCHWA MEDICO™ will be used in this Clinical Investigation during the active VNS periods. The active VNS stimulation will be applied in the hollow of the left outer ear on the auricular branch of the vagus nerve (cymba conchae), a session of 1 hour of stimulation per week, at a weak intensity value (between 2 to 5 mA). During the placebo VNS periods, VNS placebo stimulation will be performed under the same conditions and parameters as active VNS stimulation, but at a different site: the left ear lobule according to previously published methods (Frangos et al., 2015, Fang et al., 2017). All randomized patients will be followed up until the end of their stimulation periods. Data collection for the assessment of endpoints will be performed by biochemistry tests and questionnaires in all patients at the first and the last visit of each period.

Official Title
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Randomized Cross Over Study Assessing the Effectiveness of Non-invasive Vagus Nerve Stimulation in Patients With Axial Spondyloarthritis Resistant to Biotherapies

Conditions
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Axial Spondyloarthritis

Intervention / Treatment
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* Device: active stimulation then placebo stimulation
* Device: placebo stimulation then active stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient from 18 to 90 years with axial SpA, meeting the ASAS classification criteria, followed for at least one year, with presence of radiological sacro-illitis (ankylosing spondylitis) or not; Patient suffering active SpA, with or without treatment, having a total BASDAI score ≥ 4 (0-10) at baseline and a score of global pain ≥ 4 (0-10); SpA insufficiently relieved despite optimal drug management for at least 6 months including at least 2 different NSAIDs at the maximum tolerated dose for at least 3 months (or less in case of intolerance) and at least two lines of biotherapies or discontinued SpA treatments due to intolerance, contraindication. Exclusion Criteria: Patient under guardianship; Cardiac arrhythmia; Patients with cochlear implant; Patients with known heart disease; Hypotension; Asthmatic patients; Refusal to participate in the study or to sign the informed consent; Pregnant or breastfeed woman; No affiliation to a social security scheme; Previous VNS treatment; Incapacity to attend the weekly appointment during the study period; 12- Head trauma with fracture of rock. In case of skin lesions of the left ear, recruitment will be delayed until these lesions are healed.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: active stimulation then placebo stimulation<br>VNS active stimulation: Use of device (Tens Eco Plus SCHWA MEDICO™) for 8 weeks, then VNS placebo for 8 weeks. The two stimulation periods will be separated by a 4 +/- 1 weeks wash-out period. The VNS placebo stimulation period being the control one. | Device: active stimulation then placebo stimulation<br>* The active VNS stimulation will be applied in the hollow of the left outer ear on the auricular branch of the vagus nerve (cymba conchae), a session of 1 hour of stimulation per week, at a weak intensity value (between 2 to 5 mA), depending on the tolerance of each patient. A transcutaneous vagus nerve stimulator Tens Eco Plus SCHWA MEDICO™ France with the Garches Azabou-Bao vagal electrode (the G electrode) will be used in this Clinical Investigation. VNS placebo stimulation will be performed under the same conditions and parameters as active VNS stimulation, but at a different site: the left ear lobule according to previously published methods (Fang et al. 2017, Frangos et al. 2015). The two stimulation periods will be separated by a 4 weeks wash-out period.<br>|
| Experimental: Group B: placebo stimulation then active stimulation<br>VNS placebo for 8 weeks, then VNS active stimulation Use of device (Tens Eco Plus SCHWA MEDICO™) for 8 weeks. The two stimulation periods will be separated by a 4 +/- 1 weeks wash-out period. The VNS placebo stimulation period being the control one. | Device: placebo stimulation then active stimulation<br>* VNS placebo stimulation will be performed under the same conditions and parameters as active VNS stimulation, but at a different site: the left ear lobule according to previously published methods (Fang et al. 2017, Frangos et al. 2015). The active VNS stimulation will be applied in the hollow of the left outer ear on the auricular branch of the vagus nerve (cymba conchae), a session of 1 hour of stimulation per week, at a weak intensity value (between 2 to 5 mA), depending on the tolerance of each patient. A transcutaneous vagus nerve stimulator Tens Eco Plus SCHWA MEDICO™ France with the Garches Azabou-Bao vagal electrode (the G electrode) will be used in this Clinical Investigation. The two stimulation periods will be separated by a 4 weeks wash-out period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change according to the ASAS Response Criteria (ASAS 20) | Assessement of efficacy of VNS treatment: for SpA patients under VNS treatment and under placebo non-specific stimulation, to demonstrate improvement of VNS treatment, according to ASAS20 definition, greater than placebo non-specific stimulation. ASAS20 Response is defined as follows: an improvement of 20% compared to baseline and an absolute improvement from baseline of at least 1 unit, in 3 of the 4 ASAS domains: as well as no baseline deterioration of 20% and of at least one unit in the fourth domain. | At baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement according to ASAS40 criteria | A 40% improvement ASAS40 after VNS treatment | at baseline, 3 months, 4 months ans 7 months | 
| Partial remission | Partial remission according to the ASAS definition | at baseline, 3 months, 4 months ans 7 months | 
| Improvement of BASFI |  | at baseline, 3 months, 4 months ans 7 months | 
| Serum CRP level | Changes of C-reactive protein (CRP) serum level | at baseline, 3 months, 4 months ans 7 months | 
| Serum ESR | Changes of serum erythrocytes sedimentation rate (ESR) | at baseline, 3 months, 4 months ans 7 months | 
| ASDAS_CRP | Changes of ASDAS_CRP | at baseline, 3 months, 4 months ans 7 months | 
| ASDAS_ESR | Changes of ASDAS_ESR | at baseline, 3 months, 4 months ans 7 months | 
| Circulating cytokines level of IL-6, IL-17, IL-23, IL-33, and MMP-3-8-9 | Difference in levels of circulating cytokines: IL-6, IL-23,IL-17, IL-33 and of matrix metallopeptidases (MMP3-8-9) | at baseline, 3 months, 4 months ans 7 months | 
| Quality of life: SF-36 | Assessement of quality of life: according to the following indexes: SF-36 | at baseline, 3 months, 4 months ans 7 months | 
| Quality of life: AS Quality of Life (ASQOL) | Assessement of quality of life: according to the AS Quality of Life (ASQOL). | at baseline, 3 months, 4 months ans 7 months | 
| ASAS-HI | Change of Health Index of patient with SpA (ASAS HI) | at baseline, 3 months, 4 months ans 7 months | 
| WPI Productivity Index | Change of Health Index of patient with the WPI Productivity Index | at baseline, 3 months, 4 months ans 7 months | 
| Fatigue severity evaluation | A visual analogue scale (VAS) will be used to evaluate fatigue severity | at baseline, 3 months, 4 months ans 7 months | 
| Global Pain assessment | Global Pain assessment will be used. | at baseline, 3 months, 4 months ans 7 months | 
| Anxiety and Depression Assessment | Anxiety and Depression Assessment : HAD | at baseline, 3 months, 4 months ans 7 months | 
| BASMI |  | at baseline, 3 months, 4 months ans 7 months | 
| Non-steroidal anti-inflammatory drugs (NSAID) intake score | Change of non-steroidal anti-inflammatory drugs (NSAID) intake score | at baseline, 3 months, 4 months ans 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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axial spondyloarthritis, vagus nerve stimulation