Modelling and Control of Non-invasive Vagus Nerve Stimulation for Autoimmune Diseases (1A)

Hospital Clinic of Barcelona18 enrolled

Overview

The overall goal of this clinical trial is to evaluate the causality relationship between the non vagus nerve stimulation waveform parameters and the therapeutic effect. Thus, unlocking a pathway to optimize parameters that maximize the benefits of therapy and minimize unwanted side effects. The experimental design includes the analysis of physiological signals, clinical biomarkers of disease, and clinical outcomes to determine the most effective measures for the monitoring, optimization, and personalization of non vagus nerve stimulation in systemic lupus erythematosus disease.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

SCREENING

Masking

SINGLE

Enrollment

Conditions

Systemic Lupus Erythematosus Autoimmune Disorder Vagus Nerve Autonomic Disorder

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Systemic lupus erythematosus (SLE) (defined by the American College of Rheumatology- or SLICC criteria) * Musculoskeletal pain ≥ 4 on a non-anchored VAS 10 cm scale * BILAG C on Musculoskeletal Domain of the BILAG 2004 * If on corticosteroids, the dose must be stable and ≤ 10mg/day (prednisone or equivalent) for at least 28 days before baseline, * If on background immunosuppressive treatment the dose must be stable for at least 28 days before baseline * Able and willing to give written informed consent and comply with the requirements of the study protocol. Exclusion Criteria: * Treatment with rituximab within one year of baseline as it is related to lymphocyte depletion that could alter the result of the biomarker study (subjects with previous treatment with rituximab can enter study only with documentation of B cell repletion). * Treatment with cyclophosphamide within 2 months of baseline as it is related to lymphocyte depletion that could alter the result of the biomarker study. * Expectation to increase steroids and/or immunosuppressive treatment. * Anti-phospholipid syndrome. * Fibromyalgia (fibromyalgia will be defined as a score \> 13 on the Fibromyalgia Symptom Scale), chronic fatigue syndrome. * Treatment with an anti-cholinergic or sympathicomimetic medication, including over the counter medications. * Implantable electronic devices such as pacemakers, defibrillators, hearing aids, cochlear implants or deep brain stimulators. * Joint replacement within 60 days prior to study enrolment or planned within the course of the study. * Any planned surgical procedure requiring general anaesthesia within the course of the study. * Intra-articular cortisone injections within 28 days of the start of study. * Chronic inflammatory disorders apart from SLE affecting the joints. * Investigational drug and/or treatment during the 28 days or seven half-lives of the investigational drug prior to the start of study drug dosing (Day 0), whichever is the greater length of time. * Active infection including hepatitis B, hepatitis C or HIV at baseline due to high prevalence of neuropathy. * Any condition which, in the opinion of the investigator, would jeopardize the subject's safety following exposure to a study intervention. * Pregnancy or lactation. * Haemoglobin below 9.0 gm/dL (by the most recent CBC) as anaemia is related to no- neurogenic orthostatic hypotension and increases cardiovascular symptoms in COMPASS 31 scale * Comorbid disease that may require administration of corticosteroid use. * Inability to comply with study and follow-up procedures. * Known cardiac arrhythmia, severe cardiac disease or neurodegenerative disease. * Known or confirmed at baseline screening peripheral or autonomic nervous system involvement, including LES-related, toxic polyneuropathies, metabolic neuropathies (including diabetes), etc. * Previous experience with vagus nerve stimulation devices

Outcomes

Primary Outcomes

Number of patients with Systemic Lupus Erythematosus with clinical and analytic change after non-invasive vagus nerve stimulation (nVNS) at different waveform parameters

We will develop an nVNS platform with an integrated nVNS decision support system, including nVNS and physiological wearable sensors, that will optimize nVNS waveform parameters to maximize the therapeutic effect while minimizing unwanted side effects. Therapeutic effect and side effects will be measured by clinical, neurophysiological and analytic tests as described in "secondary outcome measures".

Time frame: Visit 1(baseline, exploratory study, up to 30days prior to first nVNS)

Secondary Outcomes

Blood count

Complete blood count

Time frame: Baseline, after five days of stimulation and 1 month after stimulation. Additionally, 2 and 3months after stimulation if the biomarkers and scales of activity do not return to baseline levels

Erythrocyte sedimentation rate

Marker of inflammatory conditions, mm/h

C-reactive protein

Markers of inflammatory conditions, mg/dl

Anti-dsDNA

Serological marker of activity in Systemic lupus erythematosus (SLE) ui/ml

C3, C4

Serological markers of activity in Systemic lupus erythematosus (SLE) g/l

Tumoral necrosis factor (TNF), Interleukin (IL) -6, IL-10 and Il1B

Levels of pro-inflammatory cytokines, pg/ml

High mobility group box 1 protein (HMGB1)

Levels of pro-inflammatory cytokines, ui

Alpha interferon (IFNα)

Ratios of IFNα protein, ui

EuroQol-5D (EQ-5D-5L),

EQ-5D-5L questionaries. Minimum 1, maximum 3, higher scores mean a worse outcome.

Time frame: Baseline, days 1-2-3-4-5 of nVNS, after five days of nVNS, after 2 weeks of nVNS, after3 weeks of nVSN. Additionally, 2 and 3months after stimulation if the biomarkers and scales of activity do not return to baseline levels and 1 month after nVNS.

Lupus Patient-Reported Outcome (LupusPRO)

Lupus PRO questionaries. Minimum 0, maximum 5, higher scores mean a worse outcome.

Lupus Quality of Life (LupusQoL)

Lupus QoL questionaries. Minimum 1, maximum 7, higher scores mean a worse outcome.

Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)

FACIT-F scale. Minimum 0, maximum 4, higher scores mean a worse outcome.

Fatigue Severity Scale (FSS)

FSS. Minimum 1, maximum 7, higher scores mean a worse outcome.

Composite Autonomic Symptom Score (Compass-31)

Self-scoring Compass 31 autonomic assessment. Minimum 0, maximum 100, higher scores mean a worse outcome.

28-joint count

28-joint count will be used to assess articular involvement.

Physician's Global Assessment (PGA)

PGA as non-specific activity scale. Minimum 0, maximum 3, higher scores mean a worse outcome.

Patients' Global Assessment (PtGA)

PtGA as non-specific activity scale. Minimum 0, maximum 100, higher scores mean a worse outcome.

Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)

CLASI will be used to evaluate skin involvement.Minimum 0, maximum 100, higher scores mean a worse outcome.

Numeric scale ranges (NRS)

11-point NRS scale for pain. Minimum 0, maximum 10, higher scores mean a worse outcome.

Visual Analog Scale (VAS)

VSA for pain. Minimum 0, maximum 10, higher scores mean a worse outcome.

High-frequency power, low-frequency power

Continuous electrocardiogram will be recorded at rest for 5 minutes for heart rate variability (HRV) analysis (high-frequency power HF, low-frequency power LF), m2

LF to HF power ratio

Continuous electrocardiogram will be recorded at rest for 5 minutes for heart rate variability (HRV) analysis ( LF to HF power ratio)

Cardiovagal evaluation. (Composite autonomic scoring scale)

Continuous electrocardiogram heart rate changes during deep breathing and postural changes (beats per minute).Composite autonomic scoring scale minimun 0, maximum 3, higher scores mean a worse outcome.

Vasalva ratio

Continuous electrocardiogram heart rate changes during Valsalva manoeuvre (ratio).

Sympathetic evaluation (Composite autonomic scoring scale)

Beat-to-beat blood pressure changes to isometric exercise, Valsalva manoeuvre and postural changes, (mmHg). Composite autonomic scoring scale minimun 0, maximum 4, higher scores mean a worse outcome.

Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)

Disease-specific activity scale. Minimum 0, maximum 105, higher scores mean a worse outcome.

BILAG-2004

Disease-specific activity scale. Minimum 0, maximum 32, higher scores mean a worse outcome.