Transcutaneous Vagus Nerve Stimulation in SLE

Official title

Transcutaneous Vagus Nerve Stimulation in SLE (TvSSLE)

Overview

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.

Interventions

• Device Active vagus nerve stimulation
  Patients will receive transcutaneous stimulation of the vagus nerve for 5 minutes daily for 28 consecutive days. The device is a handheld electrical pulse generator and a pair of electrodes will be placed on the skin for stimulation. The electrical pulse generator is turned on and the amplitude of stimulation increased to the greatest amount tolerated. Patients will be followed through day 57 to assess durability of the intervention.
• Device Sham vagus nerve stimulation
  Patients will receive transcutaneous stimulation of the vagus nerve for 5 minutes daily for 28 consecutive days. The device is a handheld electrical pulse generator and a pair of electrodes will be placed on the skin for stimulation. The electrical pulse generator is turned on and the amplitude of stimulation increased to the greatest amount tolerated, however, the vagus nerve will not be stimulated. Patients will be followed through day 57 to assess durability of the intervention.

Primary outcome measures

• Change in Musculoskeletal Pain From Baseline. [Time frame: 28 days]

Secondary outcome measures (12)

• Percentage of Subjects With Treatment Emergent Adverse Events. [Time frame: 57 days]
• Change in Musculoskeletal Pain From Baseline [Time frame: 5 days]
• Change in Musculoskeletal Pain From Baseline [Time frame: 57 days]
• Change in Musculoskeletal Pain From Day 29 to Day 57 [Time frame: day 29 to day 57]
• Fatigue [Time frame: 5 days]
• Fatigue [Time frame: 28 days]
• Fatigue [Time frame: 57 days]
• Fatigue [Time frame: day 29 to day 57]
• Tender Joint Reduction [Time frame: 5 days]
• Tender Joint Reduction [Time frame: 28 days]
• Tender Joint Reduction [Time frame: 57 days]
• Tender Joint Reduction [Time frame: Day 29 to Day 57]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06987565 · 21-0331

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗