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

Systemic Lupus Erythematosus Clinical Trial

— VaNeSA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05704153
• Other study ID #: PID2020-117171RA-I00-1A
• Status: Recruiting
• Phase: N/A
• Start date: September 30, 2022
• Est. completion date: October 2024

Study information

• Verified date: February 2024
• Source: Hospital Clinic of Barcelona
• Contact: Judith Navarro, MD
• Phone: 0034
• Email: JNAVARR1[@]clinic.cat
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: October 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Autoimmune Diseases
• Autoimmune Disorder
• Autonomic Nervous System Diseases
• Lupus Erythematosus, Systemic
• Primary Dysautonomias
• Systemic Lupus Erythematosus
• Vagus Nerve Autonomic Disorder

Intervention

Device:
• Parasym 1Hz
Transcutaneous auricular vagus nerve stimulation of 1Hz
• Parasym 30Hz
Transcutaneous Auricular Vagus Nerve Stimulation of 30Hz
• Sham Intervention
Sham stimulation

Locations

Country	Name	City	State
Spain	Hospital Clinic	Barcelona

Sponsors (5)

Lead Sponsor	Collaborator
Hospital Clinic of Barcelona	Hospital Mutua de Terrassa, Imperial College London, Johns Hopkins University, Universitat de Girona

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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".	Visit 1(baseline, exploratory study, up to 30days prior to first nVNS)
Secondary	Blood count	Complete blood count	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
Secondary	Erythrocyte sedimentation rate	Marker of inflammatory conditions, mm/h	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
Secondary	C-reactive protein	Markers of inflammatory conditions, mg/dl	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
Secondary	Anti-dsDNA	Serological marker of activity in Systemic lupus erythematosus (SLE) ui/ml	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
Secondary	C3, C4	Serological markers of activity in Systemic lupus erythematosus (SLE) g/l	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
Secondary	Tumoral necrosis factor (TNF), Interleukin (IL) -6, IL-10 and Il1B	Levels of pro-inflammatory cytokines, pg/ml	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
Secondary	High mobility group box 1 protein (HMGB1)	Levels of pro-inflammatory cytokines, ui	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
Secondary	Alpha interferon (IFNa)	Ratios of IFNa protein, ui	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
Secondary	EuroQol-5D (EQ-5D-5L),	EQ-5D-5L questionaries. Minimum 1, maximum 3, higher scores mean a worse outcome.	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.
Secondary	Lupus Patient-Reported Outcome (LupusPRO)	Lupus PRO questionaries. Minimum 0, maximum 5, higher scores mean a worse outcome.	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
Secondary	Lupus Quality of Life (LupusQoL)	Lupus QoL questionaries. Minimum 1, maximum 7, higher scores mean a worse outcome.	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
Secondary	Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)	FACIT-F scale. Minimum 0, maximum 4, higher scores mean a worse outcome.	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
Secondary	Fatigue Severity Scale (FSS)	FSS. Minimum 1, maximum 7, higher scores mean a worse outcome.	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
Secondary	Composite Autonomic Symptom Score (Compass-31)	Self-scoring Compass 31 autonomic assessment. Minimum 0, maximum 100, higher scores mean a worse outcome.	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
Secondary	28-joint count	28-joint count will be used to assess articular involvement.	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
Secondary	Physician's Global Assessment (PGA)	PGA as non-specific activity scale. Minimum 0, maximum 3, higher scores mean a worse outcome.	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
Secondary	Patients' Global Assessment (PtGA)	PtGA as non-specific activity scale. Minimum 0, maximum 100, higher scores mean a worse outcome.	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
Secondary	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.	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
Secondary	Numeric scale ranges (NRS)	11-point NRS scale for pain. Minimum 0, maximum 10, higher scores mean a worse outcome.	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
Secondary	Visual Analog Scale (VAS)	VSA for pain. Minimum 0, maximum 10, higher scores mean a worse outcome.	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
Secondary	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	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
Secondary	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)	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
Secondary	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.	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
Secondary	Vasalva ratio	Continuous electrocardiogram heart rate changes during Valsalva manoeuvre (ratio).	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
Secondary	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.	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
Secondary	Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)	Disease-specific activity scale. Minimum 0, maximum 105, higher scores mean a worse outcome.	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
Secondary	BILAG-2004	Disease-specific activity scale. Minimum 0, maximum 32, higher scores mean a worse outcome.	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

External Links

•   Framework of the general project lead by Iván Contreras : VaNeSA