Transcutaneous Vagus Nerve Stimulation in SLE

Phase 2

Not yet recruiting

• Conditions: Systemic Lupus Erythematosus

• Registration Number: NCT06987565
• Lead Sponsor: Northwell Health

Brief Summary

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease. Joint and muscle pain and fatigue are extremely common among patients and contribute to a reduced quality of life. Available therapies may be associated with significant side effects and many patients do not achieve an adequate response to these treatments. Therefore, there is an unmet need to develop new strategies to reduce pain and fatigue. Filling this need would significantly improve patients' quality of life. This trial will evaluate the effects of a novel approach, stimulating the vagus nerve, a nerve originating in the brain as a potential therapeutic intervention for treatment of musculoskeletal pain and fatigue. Vagus nerve stimulation has multiple beneficial effects and is one of the body's own ways to modulate the immune system. One can stimulate the vagus nerve via the skin at the neck or at specific locations in the ear, (transcutaneous vagus nerve stimulation: tcVNS). We recently completed a short, small scale randomized, placebo controlled trial of tcVNS in patients with SLE and observed dramatic benefits on musculoskeletal pain and fatigue. The treatment was safe without side effects. We are therefore proposing a longer trial to validate our initial findings and to look at durability. In this study, 18 patients with musculoskeletal pain will be followed for 2 months and will receive tcVNS or placebo (sham stimulation) for 5 minutes/day for 28 days. Patients will have a 1 out of 3 chance of receiving sham stimulation and neither the patient nor the evaluating investigator will know the actual treatment. The stimulations are self-administered, are non-painful and have not been associated with serious risks. After 28 days of stimulation, treatment will be discontinued and patients will be monitored for an additional 28 days to evaluate durability. Pain, fatigue and disease activity will be evaluated as well as possible side effects will be monitored throughout the trial. This study will also explore biologic mechanisms that may be responsible for the potential clinical effects. This will include possible effects of stimulation on gut permeability and the stool microbiome, areas that may play a significant role contributing to SLE disease and its manifestations. The development of an effective treatment without significant side effects would be extremely valuable and a significant advance for patients with SLE. If efficacious, tcVNS offers a non-toxic, non-immunosuppressive strategy to control two of the most common symptoms of this disease.

Detailed Description

Musculoskeletal (MS) pain and fatigue are common symptoms of patients with Systemic Lupus Erythematosus (SLE) affecting up to 95% and contributing to a reduced quality of life. Safe and efficacious treatment remains an unmet need for these disease manifestations. Stimulation of the vagus nerve results in beneficial effects in patients. We recently completed a short , small scale, randomized, sham-controlled, double blind clinical trial of transcutaneous vagus nerve stimulation (taVNS) in patients with SLE. The clinical benefit on MS pain and fatigue was dramatic. We now propose a randomized sham controlled clinical trial assessing the efficacy and durability of a longer exposure to taVNS (28 days in comparison to the 4 day exposure in the previous trial) in 18 patients randomized 2: 1 with musculoskeletal pain. After 28 days of stimulation, the treatment will be discontinued and patients will be monitored for an additional 28 days to evaluate the treatment's durability. Pain, fatigue, disease activity (global and musculoskeletal) and safety will be evaluated and safety will be monitored throughout the trial. In this clinical trial we will also explore potential biologic mechanisms and pathways by which taVNS exerts ifs effects in SLE, including potential effects on gut permeability and the microbiome.

Study Timeline

• Study First Submitted: 2025-04-23
• Status Verified: 2025-05
• Study Start: 2025-05-15
• Study First Submitted QC: 2025-05-15
• Last Update Submitted: 2025-05-15
• Study First Posted: 2025-05-23
• Last Update Posted: 2025-05-23
• Primary Completion: 2026-11
• Study Completion: 2027-05

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

• SLE (defined by the ACR or SLICC criteria),
• Musculoskeletal pain ≥ 4 on a non-anchored VAS 10 cm scale,
• BILAG C or greater on the Musculoskeletal Domain of the BILAG 2004,
• If on corticosteroids, the dose must be stable and ≤ 10 mg/day (prednisone or equivalent) for at least 14 days before baseline,
• If on background immunosuppressive treatment the dose must be stable for at least 28 days before baseline,
• If on NSAIDS, the dose must be stable for at least 7 days before baseline and the subject must be willing not to change the dose during the trial (except for toxicity),
• Able and willing to give written informed consent and comply with the requirements of the study protocol.

Exclusion Criteria

• Initiation of immunosuppressive or antimalarial treatment within 3 months of baseline,
• Treatment with cyclophosphamide within 2 months of baseline,
• Initiation of anifrolumab within 3 months of baseline
• Initiation of belimumab within 6 months of baseline,
• Expectation to increase steroids and/or immunosuppressive treatment,
• Anti-phospholipid syndrome,
• Fibromyalgia,
• Treatment with an anti-cholinergic medication, including over the counter medications,
• Any implantable electronic devices including pacemakers, defibrillators, hearing aids, cochlear implants or deep brain stimulators,
• Current tobacco or nicotine user (to limit potential confounding effects of exposure to nicotine),
• Joint replacement within 60 days prior to study enrollment or planned within the course of the study,
• Any planned surgical procedure requiring general anesthesia 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 or hepatitis C at baseline,
• Any condition which, in the opinion of the investigator, would jeopardize the subject's safety following exposure to a study intervention,
• Pregnancy or lactation (Pregnancy status will be determined via serum blood test & lactation will be determined via self-report),
• Comorbid disease that has previously required administration of corticosteroid use,
• Known allergy to mannitol or lactulose,
• Chronic treatment with narcotic medication,
• Prior receipt of transauricular vagus nerve stimulation in a clinical trial,
• Inability to comply with study and follow-up procedures.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Change in Musculoskeletal Pain From Baseline.	28 days	Patients rate their musculoskeletal pain by making a mark on a 10cm anchored Visual Analog Scale where 0=no musculoskeletal pain and 10 =worst possible musculoskeletal pain.

Secondary Outcome Measures

Name	Time	Method
Musculoskeletal disease activity--physician	Days 28 to 57	Musculoskeletal disease activity will be assessed by the physician investigator by an anchored visual analog scale.ranging from 0 to 10 with higher scores signifying higher musculoskeletal disease activity.
Morning Stiffness	Days 29 to 57	Morning stiffness will be assessed by patients by an anchored visual analog scale.ranging from 0 to 10 with higher scores signifying greater morning stiffness.
Patient assessment of response	Day 57	Patient assessment of response will be determined by a 5 component Likert scale by the patient.
Health Related Quality of Life (HRQoL))	Days 29 to 57	HRQoL will be evaluated using the LupusQoL, a validated SLE specific index which assesses 8 domains including physical health, emotional health, body image, pain, planning, fatigue, intimate relationships, and burden to others. Higher scores correspond to worse quality-of-life.
Depression	Days 29 to 57	Beck Depression Inventory (BDI) will assess depression. The BDI is a 21 item questionnaire measuring the severity of depression. Higher scores indicate greater levels of depression.
Polysymptomatic distress	Days 29 to 57	Polysymptomatic distress will be assessed by the Fibromyalgia Symptom Score (FSS), a patient reported outcome measuring the extent of polysymptomatic distress on a scale ranging from 0-31. Higher scores correspond to greater polysymptomatic distress.
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K)	Days 29 to 57	SLEDAI-2K is a 24 item index which are scored by an investigator as either present or absent. Items include clinical and laboratory features of SLE. Higher scores correspond to greater disease activity.
BILAG (British Isles Lupus Assessment Group) 2004	Days 29 to 57	BILAG 2004 index assesses SLE disease activity in nine organ symptoms. Each domain is categorized into 1 of 5 levels (A, B, C, D, E). Lower letters (e.g. A) indicate more active disease.
CLASI (Cutaneous LE Disease Area and Severity Index)	Days 29 to 57	CLASI assesses SLE skin disease activity and damage. Higher scores indicate greater levels of cutaneous disease.
Musculoskeletal disease activity--patient	Days 29 to 57	Musculoskeletal disease activity will be assessed by patients by an anchored visual analog scale.ranging from 0 to 10 with higher scores signifying higher musculoskeletal disease activity.
Anxiety	Days 29 to 57	Promis Anxiety Short Form will assess anxiety. It is an 8 item questionaire assessing components related to anxiety including fear, anxious misery, hyperarousal, and somatic symptoms. Higher scores indicate greater levels of anxiety.
Percentage of Subjects With Treatment Emergent Adverse Events.	57 days	The percentage of participants with grade 2 or higher or specific grade 1 treatment emergent adverse events will be assessed using the NCI-CTAEversion4.; The percentage of participants with grade 2 or higher treatment emergent adverse events will be assessed using the NCI-CTAEversion4.; The percentage of participants with grade 2 or higher treatment emergent adverse events will be assessed using the NCI-CTAEversion4.
Change in Musculoskeletal Pain From Baseline	57 days	Patients rate their musculoskeletal pain by making a mark on a 10cm anchored Visual Analog Scale where 0=no musculoskeletal pain and 10 =worst possible musculoskeletal pain.
Change in Musculoskeletal Pain From Day 29 to Day 57	day 29 to day 57	Patients rate their musculoskeletal pain by making a mark on a 10cm anchored Visual Analog Scale where 0=no musculoskeletal pain and 10 =worst possible musculoskeletal pain.
Fatigue	day 29 to day 57	Change from Day 29 fatigue to Day 57 will be measured using the FACIT F (Functional Assessment of Chronic Illness Therapy) questionnaire. The score ranges from 0 to 52, a higher score indicates less fatigue.
Tender Joint Reduction	Day 29 to Day 57	The percentage of tender joints reduced from day 29 to day 57 will be assessed by an investigator upon examining 68 potential tender joints.
Physician Global Assessment of Disease Activity (PGA)	Days 29 to 57	Change in PGA from day 29 to day 57; PGA is an anchored visual analog scale.ranging from 0 to 3 with higher scores signifying higher disease activity.
Physician assessment of response	Day 57	Patient assessment of response will be determined by a 5 component Likert scale by the physician investigator.
Lupus Low Disease Activity State (LLDAS)	Day 57	LLDAS is a state achieved when there are minimal signs or symptoms of lupus disease activity while the patient is on low dose corticosteroids and stable therapy.
SRI-4	Day 57	SRI-4 is a composite categorical response measure of improvement in SLE disease activity from a comparator timepoint/baseline. Achievement of the SRI-4 indicates a clinically meaningful response.
Swollen joint reduction	Day 29 to Day 57	The percentage of swollen joints reduced from Day 29 to Day 57 assessed by an investigator upon examining 66 potential swollen joints. Data shown for seven taVNS and five SS subjects with swollen joints at baseline.
Patient Global Assessment of Disease (PtGA)	Days 29 to 57	Change in PtGA from day 29 to 57; PtGA is an anchored visual analog scale.ranging from 0 to 10 with higher scores signifying higher disease activity.
Pain intensity	Days 29 to 57	Pain intensity assessed by the PROMIS Pain Intensity Form 1a which asks subjects to mark a scale rating the average pain intensity over the past 7 days. The rating scale consists of whole numbers from 1 to 10. The PROMIS Pain Intensity Scale is a series of 3 questions that assess pain intensity at its worst, at its average, and at current moment. A higher score indicates higher levels of pain intensity.
Pain interference	Days 29 to 57	Pain interference will be assessed by requesting subjects to answer the PROMIS Pain Interference Short Form 8a. The PROMIS Pain Interference Short Form 8a is a series of 8 questions which asks how much has pain interfered with different aspects of activities of daily living over the previous 7 days