Clinical trial NCT06987565: Transcutaneous Vagus Nerve Stimulation in SLE
Official title: Transcutaneous Vagus Nerve Stimulation in SLE (TvSSLE)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Keywords: Systemic Lupus Erythematosus
Pain
Vagus nerve stimulation
Lead sponsor: Northwell Health
Sponsor class: OTHER
Collaborators: name: Lupus Research Alliance
First posted: 2025-05-23
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in Musculoskeletal Pain From Baseline.
timeFrame: 28 days
Secondary outcomes:
measure: Percentage of Subjects With Treatment Emergent Adverse Events.
timeFrame: 57 days
measure: Change in Musculoskeletal Pain From Baseline
timeFrame: 5 days
measure: Change in Musculoskeletal Pain From Baseline
timeFrame: 57 days
measure: Change in Musculoskeletal Pain From Day 29 to Day 57
timeFrame: day 29 to day 57
measure: Fatigue
timeFrame: 5 days
measure: Fatigue
timeFrame: 28 days
measure: Fatigue
timeFrame: 57 days
measure: Fatigue
timeFrame: day 29 to day 57
measure: Tender Joint Reduction
timeFrame: 5 days
measure: Tender Joint Reduction
timeFrame: 28 days
measure: Tender Joint Reduction
timeFrame: 57 days
measure: Tender Joint Reduction
timeFrame: Day 29 to Day 57
measure: Swollen joint reduction
timeFrame: 5 days
measure: Swollen joint reduction
timeFrame: 28 days
measure: Swollen joint reduction
timeFrame: 57 days
measure: Swollen joint reduction
timeFrame: Day 29 to Day 57
measure: Physician Global Assessment of Disease Activity (PGA)
timeFrame: Day 5
measure: Physician Global Assessment of Disease Activity (PGA)
timeFrame: Day 28
measure: Physician Global Assessment of Disease Activity (PGA)
timeFrame: Day 57
measure: Physician Global Assessment of Disease Activity (PGA)
timeFrame: Days 29 to 57
measure: Patient Global Assessment of Disease (PtGA)
timeFrame: Day 5
measure: Patient Global Assessment of Disease (PtGA)
timeFrame: Day 28
measure: Patient Global Assessment of Disease (PtGA)
timeFrame: Day 57
measure: Patient Global Assessment of Disease (PtGA)
timeFrame: Days 29 to 57
measure: Pain intensity
timeFrame: 5 days
measure: Pain intensity
timeFrame: 28 days
measure: Pain intensity
timeFrame: 57 days
measure: Pain intensity
timeFrame: Days 29 to 57
measure: Pain interference
timeFrame: 5 days
measure: Pain interference
timeFrame: 28 days
measure: Pain interference
timeFrame: 57 days
measure: Pain interference
timeFrame: Days 29 to 57
measure: Health Related Quality of Life (HRQoL))
timeFrame: 28 days
measure: Health Related Quality of Life (HRQoL))
timeFrame: Day 57
measure: Health Related Quality of Life (HRQoL))
timeFrame: Days 29 to 57
measure: Anxiety
timeFrame: Day 29
measure: Anxiety
timeFrame: Day 57
measure: Anxiety
timeFrame: Days 29 to 57
measure: Depression
timeFrame: Day 28
measure: Depression
timeFrame: Day 57
measure: Depression
timeFrame: Days 29 to 57
measure: Polysymptomatic distress
timeFrame: Day 29
measure: Polysymptomatic distress
timeFrame: Day 57
measure: Polysymptomatic distress
timeFrame: Days 29 to 57
measure: Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K)
timeFrame: Day 28
measure: Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K)
timeFrame: Day 57
measure: Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K)
timeFrame: Days 29 to 57
measure: BILAG (British Isles Lupus Assessment Group) 2004
timeFrame: Day 28
measure: BILAG (British Isles Lupus Assessment Group) 2004
timeFrame: Day 57
measure: BILAG (British Isles Lupus Assessment Group) 2004
timeFrame: Days 29 to 57
measure: CLASI (Cutaneous LE Disease Area and Severity Index)
timeFrame: Day 28
measure: CLASI (Cutaneous LE Disease Area and Severity Index)
timeFrame: Day 57
measure: CLASI (Cutaneous LE Disease Area and Severity Index)
timeFrame: Days 29 to 57
measure: Musculoskeletal disease activity--patient
timeFrame: Day 5
measure: Musculoskeletal disease activity--patient
timeFrame: Day 29
measure: Musculoskeletal disease activity--patient
timeFrame: Day 57
measure: Musculoskeletal disease activity--patient
timeFrame: Days 29 to 57
measure: Musculoskeletal disease activity--physician
timeFrame: Day 5
measure: Musculoskeletal disease activity--physician
timeFrame: Day 28
measure: Musculoskeletal disease activity--physician
timeFrame: Day 57
measure: Musculoskeletal disease activity--physician
timeFrame: Days 28 to 57
measure: Morning Stiffness
timeFrame: Day 5
measure: Morning Stiffness
timeFrame: Day 28
measure: Morning Stiffness
timeFrame: Day 57
measure: Morning Stiffness
timeFrame: Days 29 to 57
measure: Patient assessment of response
timeFrame: Day 5
measure: Patient assessment of response
timeFrame: Day 28
measure: Patient assessment of response
timeFrame: Day 57
measure: Physician assessment of response
timeFrame: Day 5
measure: Physician assessment of response
timeFrame: Day 28
measure: Physician assessment of response
timeFrame: Day 57
measure: Lupus Low Disease Activity State (LLDAS)
timeFrame: Day 28
measure: Lupus Low Disease Activity State (LLDAS)
timeFrame: Day 57
measure: SRI-4
timeFrame: Day 28
measure: SRI-4
timeFrame: Day 57
Other outcomes:
measure: Functional gut permeability
timeFrame: Day 28
measure: Stool microbiome
timeFrame: Day 28
measure: Gut permeability: serum I-FABP, zonulin and LPS, and by stool calprotectin and zonulin
timeFrame: Day 28
measure: Gut permeability: zonulin
timeFrame: Day 28
measure: Gut permeability: Lipopolysaccharide (LPS)
timeFrame: Day 28
measure: Gut permeability: Stool calprotectin
timeFrame: Day 28
measure: Gut permeability: Stool zonulin
timeFrame: Day 28
measure: Oxidative stress
timeFrame: Day 28
measure: Oxidative stress
timeFrame: Day 57
measure: Neurotrophins
timeFrame: Day 28
measure: Neurotrophins
timeFrame: Day 57
measure: Neurotrophins
timeFrame: Days 29 to 57
measure: Kynurenine pathway metabolites
timeFrame: Day 28
measure: Kynurenine pathway metabolites
timeFrame: Day 57
measure: Kynurenine pathway metabolites
timeFrame: Days 28 to 57
measure: Neuropeptides
timeFrame: Day 28
measure: Neuropeptides
timeFrame: Day 57
measure: Neuropeptides
timeFrame: Days 29 to 57
measure: Erythrocyte Sedimentation Rate (ESR)
timeFrame: Day 5
measure: Erythrocyte Sedimentation Rate (ESR)
timeFrame: Day 28
measure: Erythrocyte Sedimentation Rate (ESR)
timeFrame: Day 57
measure: Erythrocyte Sedimentation Rate (ESR)
timeFrame: Days 28 to 57
measure: Complement component 3 (C3)
timeFrame: Day 28
measure: Complement component 3 (C3)
timeFrame: Day 57
measure: Complement component 3 (C3)
timeFrame: Days 28 to 57
measure: Complement component 4 (C4)
timeFrame: Day 28
measure: Complement component 4 (C4)
timeFrame: Day 57
measure: Complement component 4 (C4)
timeFrame: Days 28 to 57
measure: Anti-DNA antibodies
timeFrame: Day 28
measure: Anti-DNA antibodies
timeFrame: Day 57
measure: Anti-DNA antibodies
timeFrame: Days 28 to 57
Locations:
Study officials:
affiliation: Northwell Health
name: Cynthia Aranow, MD
role: PRINCIPAL_INVESTIGATOR
References: