Splenic Stimulation for Rheumatoid Arthritis
Recruiting in Palo Alto (17 mi)
+11 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Galvani Bioelectronics
Must be taking: Conventional DMARDs
Disqualifiers: Psychiatric disease, Substance abuse, Tuberculosis, HIV, others
No Placebo Group
Breakthrough Therapy
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?This study will evaluate the safety, tolerability, and effects of stimulating the splenic neurovascular bundle (NVB) with the Galvani System, which consists of a lead, implantable pulse generator, external components and accessories. The study will consist of 4 study periods, including a Randomized Control Trial period (Period 1), an Open Label period (Period 2), a Treat-to-target period (Period 3), and a Long-term Follow-up period (Period 4). Participants eligible for implant will have active rheumatoid arthritis (RA) and have an inadequate response or intolerance to at least two biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) or JAK inhibitors (JAKis). A sufficient number of participants will be enrolled so that approximately 28 participants will undergo device implantation.
Will I have to stop taking my current medications?
The trial does not specify if you must stop taking your current medications, but it mentions a 'washout period' for previously used biological DMARDs or JAK inhibitors. This means you might need to stop these specific medications for a certain time before starting the trial.
What data supports the effectiveness of the treatment involving Splenic Stimulation for Rheumatoid Arthritis?
Research shows that targeting the immune system can be effective in treating rheumatoid arthritis, as seen with therapies that inhibit specific immune components like TNF-alpha. Advances in biotechnology and immunomodulatory strategies have shown promise in managing autoimmune diseases, suggesting that novel approaches like splenic nerve stimulation could potentially offer benefits by modulating immune responses.
12345Is splenic stimulation therapy safe for humans?
The safety of biologic therapies, which are similar to splenic stimulation, has been studied extensively, showing specific risks like infections and infusion reactions. Before starting such treatments, screening for infections like tuberculosis is standard to ensure safety.
46789How is the Galvani System treatment different from other rheumatoid arthritis treatments?
The Galvani System is unique because it uses bioelectronic medicine to stimulate the splenic nerve, targeting the body's inflammatory reflex to reduce inflammation without the use of drugs. This approach is different from traditional treatments that rely on systemic medications, offering a non-drug alternative for managing rheumatoid arthritis.
110111213Eligibility Criteria
This trial is for adults aged 22-75 with active rheumatoid arthritis (RA) who haven't responded well to at least two biologic DMARDs or JAK inhibitors, including a TNF inhibitor. They must have stopped previous RA treatments for a specific time before joining. People with implanted electrical devices, significant psychiatric issues, substance abuse problems, certain infections like COVID-19 or tuberculosis, HIV, hepatitis B/C, or those who've had vagotomy or splenectomy can't join.Inclusion Criteria
I am on standard doses of synthetic drugs for my autoimmune disease.
I have not improved after trying at least two types of advanced arthritis medication.
I have stopped my previous biologic or JAK inhibitor treatments for enough time.
+3 more
Exclusion Criteria
I have tuberculosis, whether active or not.
I have HIV or current/past hepatitis B or C.
You have a medical device implanted in your body that emits electrical signals, like a pacemaker or implantable defibrillator.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Randomized Control Trial
Participants receive either active stimulation or sham-stimulation for 12 weeks
12 weeks
Open Label
Participants who responded to stimulation continue on stimulation; others receive a market-approved RA drug for 12 weeks
12 weeks
Treat-to-target
Participants treated with dual therapy (stimulation and RA drug) for up to 24 weeks
24 weeks
Long-term Follow-up
Long-term safety follow-up for all participants for 5 years, with possible stimulation and standard of care therapies
5 years
Participant Groups
The study tests the Galvani System's safety and effects on stimulating the splenic neurovascular bundle in RA patients. It includes an initial randomized control phase where some get real stimulation and others sham (fake) treatment; followed by open label and treat-to-target periods; ending with long-term follow-up to assess outcomes.
7Treatment groups
Experimental Treatment
Placebo Group
Group I: RA drug combined with active stimulation, Period 3Experimental Treatment3 Interventions
Participants on baricitinib during Period 2 will have active stimulation added for 24 weeks
Group II: Open label active stimulation, Period 2Experimental Treatment2 Interventions
Open label active stimulation for 12 additional weeks
Group III: Open label RA Drug, Period 2Experimental Treatment2 Interventions
Open label drug treatment with baricitinib for 12 weeks
Group IV: Long-term Follow-up, Period 4Experimental Treatment2 Interventions
Standard of care treatments with or without stimulation
Group V: Active stimulation combined with RA drug, Period 3Experimental Treatment3 Interventions
Participants on active stimulation during Period 2 will have baricitinib added for 24 weeks
Group VI: Active Stimulation; Period 1Experimental Treatment2 Interventions
Active stimulation for 12 weeks
Group VII: Sham Stimulation; Period 1Placebo Group2 Interventions
Sham stimulation for 12 weeks
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Oregon Health & Science UniversityPortland, OR
Medvin Research - WhittierWhittier, CA
Medvin Research - CovinaCovina, CA
Altoona Center for Clinical ResearchAltoona, PA
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Galvani BioelectronicsLead Sponsor
NAMSACollaborator
Q2 SolutionsIndustry Sponsor
References
Therapeutic applications of nanomedicine in autoimmune diseases: from immunosuppression to tolerance induction. [2022]Autoimmune diseases are chronic, destructive diseases that can cause functional disability and multiple organ failure. Despite significant advances in the range of therapeutic agents, especially biologicals, limitations of the routes of administration, requirement for frequent long-term dosing and inadequate targeting options often lead to suboptimal effects, systemic adverse reactions and patient non-compliance. Nanotechnology offers promising strategies to improve and optimize autoimmune disease treatment with the ability to overcome many of the limitations common to the current immunosuppressive and biological therapies. Here we focus on nanomedicine-based delivery strategies of biological immunomodulatory agents for the treatment of autoimmune disorders including psoriasis, rheumatoid arthritis, systemic lupus erythematous, scleroderma, multiple sclerosis and type 1 diabetes. This comprehensive review details the concepts and clinical potential of novel nanomedicine approaches for inducing immunosuppression and immunological tolerance in autoimmune diseases in order to modulate aberrant and pathologic immune responses.
Biological therapies: a novel approach to the treatment of autoimmune disease. [2019]Biological therapies for rheumatoid arthritis (RA) make use of molecules (including derivative and recombinant forms) produced by cells of the immune system or by cells that participate in inflammatory reactions. Development of monoclonal antibodies against cell-surface structures that are lineage or subset specific has led to trials of anti-T-cell reagents in RA, but results thus far must be regarded as a significant therapeutic disappointment. A monoclonal antibody designed to interfere with the action of a cytokine, tumor necrosis factor alpha (TNF-alpha), has been studied in both open and controlled trials. Treatment with this antibody resulted in marked changes in indices of inflammation, but duration of responses may be limited by the eventual development of antibodies to the anti-TNF-alpha antibody. Immunomodulatory strategies that use the immune system to regulate autoimmune activity have been developed based on animal studies, and evaluation of oral collagen as a treatment in RA is currently underway. If successful, this approach would represent a new direction in the treatment of human autoimmune disease. In the future, use of gene therapy directed to the joint could be a powerful approach to treatment of RA. Rational use of biological therapies in RA will depend, in part, on improved understanding of the pathogenesis of this condition.
Immunomodulatory nano-preparations for rheumatoid arthritis. [2022]Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD) caused by the aberrant attack of the immune system on its own joint tissues. Genetic and environmental factors are the main reasons of immune system impairment and high incidence of RA. Although there are medications on the market that lessen disease activity, there is no known cure for RA, and patients are at risk in varying degrees of systemic immunosuppression. By transporting (encapsulating or surface binding) RA-related self-antigens, nucleic acids, immunomodulators, or cytokines, tolerogenic nanoparticles-also known as immunomodulatory nano-preparations-have the potential to gently regulate local immune responses and ultimately induce antigen-specific immune tolerance. We review the recent advances in immunomodulatory nano-preparations for delivering self-antigen or self-antigen plus immunomodulator, simulating apoptotic cell avatars in vivo, acting as artificial antigen-presenting cells, and based on scaffolds and gels, to provide a reference for developing new immunotherapies for RA.
An overview of immunomodulatory intervention in rheumatoid arthritis. [2019]In recent years there has been exceptional progress in the development of immunomodulatory interventions for the treatment of rheumatoid arthritis (RA). Part of the impetus for the creation of novel therapies for RA has come from a growing appreciation of the substantial morbidity and mortality that this chronic, progressive disease causes for affected patients. In addition, there has been the realization that currently available therapeutics are suboptimal as regards both their efficacy and tolerability. The development of newer therapies has been facilitated by two factors; a greater understanding of the immunopathogenesis of RA and progress in biotechnology that has allowed the creation of specific inhibitors and other agents. Myriad studies performed by investigators throughout the world have helped delineate the immunologic basis of RA. It appears that various components of the immune system are involved in the initiation and propagation of this systemic inflammatory disease. T-cells, and in particular activated CD4(+) 'memory' T-cells, serve a central role in orchestrating the immune response that underlies rheumatoid inflammation. Other cells, including monocytes, fibroblasts, B-cells, dendritic cells, mast cells and neutrophils also contribute significantly to various aspects of disease. Adhesion molecules mediate many intercellular interactions, thus contributing to activities such as the accrual of cells within the synovium and the activation of cells. Cytokines, small peptides that exert numerous inflammatory activities and cause many of the signs and symptoms of RA, play a crucial role. Indeed, RA may be considered a disorder of 'cytokine dysregulation' in that the activity of proinflammatory cytokines such as TNF-alpha and IL-1 is enhanced, and overwhelms the effects of antiinflammatory factors. Finally, a host of other inflammatory mediators are involved in the disease process. Thus, many components of the immune response may be attractive therapeutic targets for immunomodulatory intervention in RA. Advances in biotechnology have permitted the creation of specific inhibitors of distinct components of the immune system. Monoclonal antibodies (MAbs) have been created to target various cell surface molecules and cytokines. At first, most MAbs were murine in origin, which can present problems as regards immunogenicity. More recently, progress in molecular biologic techniques has allowed the synthesis of hybrid antibodies that are partly human. Such techniques have also allowed the creation of cytokine receptors coupled to immunoglobulin molecules, and other constructs. These agents can be modified to provide optimal characteristics in terms of half-life, immunogenicity and specificity, and this is an exciting area of new development. Progress has also been made in molecular-based agents that directly modify the genes or gene products for specific targets. To date, a number of trials assessing novel immunomodulatory therapies have been undertaken. In some cases, such as with inhibitors of TNF-alpha, the results have been dramatic and exciting. Further development and refinement may allow the introduction of these agents into the clinic in the foreseeable future, and will provide an important area for further research. In other cases, for example with therapies targeting CD4(+) molecules, the results have not been as promising as was hoped. Nevertheless, critical analysis of the results of these studies has provided insights into the pathogenesis of RA which may prove quite valuable for future trials. A number of agents are being studied actively at the present time, and it is hoped that they too may generate novel therapies for, and a greater understanding of, this difficult disease. The future for immunomodulatory intervention in RA looks very promising. Greater understanding of the intricacies of the immune response that underlie this disease should continue to yield viable, specific targets for novel therapies. Advances in biopharmaceuticals should generate treatments that maximize efficacy while minimizing toxicity. This should allow the clinician truly to modify the disease and achieve tangible improvements in the lives of RA patients.
Leukapheresis and pathogenetic mechanisms in rheumatoid arthritis. [2019]Rheumatoid Arthritis is a chronic, usually progressive inflammatory disorder of joints in which the immune system plays a central role in the pathogenesis. In its classic form, the synovial tissues from severely affected joints are densely infiltrated with HLA-DR bearing T-lymphocytes (primarily OKT4+/Leu3+ subset) and macrophage-like cells. Moreover, these tissues, as demonstrated by ex vivo culture, spontaneously produce high levels of a multitude of inflammatory mediators, such as collagenase, PGE2, interleukin 1 and fibroblast activating factors, indicating that the cells infiltrating the synovium are "activated". The action of these various inflammatory mediators on different target substances or cells (collagen, fibroblasts, chondrocytes, osteoclasts, etc.) most likely produce the characteristic pattern of joint pathology. Recent data indicate that this classic form of synovitis tends to be associated with peripheral anergy and other qualitative and quantitative abnormalities in the peripheral blood mononuclear cells. Repeated leukapheresis can induce substantial, although transient, clinical improvement in patients with these classic features, probably as a consequence of disrupting T-lymphocyte traffic. Rheumatoid synovitis, however, is highly heterogeneous, but can be categorized into subsets. For example, a subset of patients with highly active clinical rheumatoid arthritis exists which do not exhibit the classic features of disease. Synovial tissues from this patient subset are sparsely infiltrated by T-lymphocytes but contain mainly macrophages and fibroblasts, as well as prominent lining layer fibrin deposition.(ABSTRACT TRUNCATED AT 250 WORDS)
[Safe use of biological therapies for the treatment of rheumatoid arthritis and spondyloarthritides]. [2017]The treatment of autoimmune rheumatic diseases has gradually improved over the last half century, which has been expanded with the contribution of biological therapies or immunobiopharmaceuticals. However, we must be alert to the possibilities of undesirable effects from the use of this class of medications. The Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia/SBR) produced a document based on a comprehensive literature review on the safety aspects of this class of drugs, specifically with regard to the treatment of rheumatoid arthritis (RA) and spondyloarthritides. The themes selected by the participating experts, on which considerations have been established as the safe use of biological drugs, were: occurrence of infections (bacterial, viral, tuberculosis), infusion reactions, hematological, neurological, gastrointestinal and cardiovascular reactions, neoplastic events (solid tumors and hematologic neoplasms), immunogenicity, other occurrences and vaccine response. For didactic reasons, we opted by elaborating a summary of safety assessment in accordance with the previous themes, by drug class/mechanism of action (tumor necrosis factor antagonists, T-cell co-stimulation blockers, B-cell depletors and interleukin-6 receptor blockers). Separately, general considerations on safety in the use of biologicals in pregnancy and lactation were proposed. This review seeks to provide a broad and balanced update of that clinical and experimental experience pooled over the last two decades of use of immunobiological drugs for RA and spondyloarthritides treatment.
The future use of biologic therapies in combination for the treatment of rheumatoid arthritis. [2005]The complexity of the immune system, exemplified by the pleiotropic effects of many cytokines and the redundancy of regulatory networks controlling immune responses, suggests that single therapeutic interventions will offer transient or less than clinically meaningful benefit. Theoretically, combination therapy using 2 or more biologic agents will modulate important symptomatic and objective manifestations of rheumatoid arthritis (RA). Data from animal models suggest that use of biologic agents in combination can be synergistic and may alter the severity and course of disease. Although combinations of biologic agents have yet to be used in human disease, successful examples employing immunosuppressive agents exist: cyclosporin (CsA) with methotrexate in patients with persistent active RA, as well as azathioprine and/or mycophenolate mofitil with CsA in organ transplantation and acute graft rejection. There are many arguments against the use of combination biologic therapies including acute infusion related toxicities, infection, malignancy, autoimmune manifestations, and expense. While caution dictates that phase I-II clinical trials be performed in patients with longstanding, refractory disease, subsequent trials should be conducted in patients with earlier, more responsive disease. Successful combination biologic therapies must afford sufficient duration of benefit (at least 6, preferably 12 months), cost comparable to approved 2nd line agents, ease of treatment, and an acceptable safety profile.
[Treatment of rheumatoid arthritis and spondylarthritis with biologics]. [2022]Biologics are an integral part of modern strategies for treatment of rheumatoid arthritis (RA) and spondylarthritis (SpA), including psoriatic arthritis (PsA). Biologics are biotechnologically produced proteins that have inhibiting effects on humoral and cellular components of rheumatic inflammation. Substance classes used in rheumatology are tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL‑6, IL-12, IL-17 and IL-23 inhibitors effective against cytokines as well as the T lymphocyte activation inhibitor abatacept and the B lymphocyte-depleting rituximab. There are clear recommendations for the use of biologics for RA patients inadequately responding to one or more conventional synthetic disease-modifying antirheumatic drugs and for ankylosing spondylitis (AS) and nonradiographical axial SpA patients with an inadequate response to at least two nonsteroidal antirheumatic drugs. For PsA the recommended use depends on the most prominent manifestations in each case. Treatment with biologics should follow the treat to target principle, with a defined and validated treatment target. Treatment in cases of RA and SpA should target remission or at least a low or minimum disease activity. The safety of treatment with biologics has been intensively investigated. There are very specific contraindications for individual substance classes with a focus on an increased risk of infections. The standard procedure before starting treatment with biologics includes the exclusion of latent tuberculosis and hepatitis B. The TNF-alpha inhibitors have a protective effect with respect to myocardial infarction, stroke and venous thromboembolism.
Gene therapy for arthritis--where do we stand? [2018]The successful use of biologicals in the treatment of rheumatoid arthritis, psoriatic arthritis and spondyloarthritis has had a major impact on the management of these conditions. The challenge in the development of gene therapy as an alternative to these current treatments is to demonstrate that such therapy is more advantageous for patients from the therapeutic and safety points of view. Also, it will need to be demonstrated that gene therapy for the arthritides is economically feasible and that patient populations worldwide will be able to access these treatments.
Harnessing the Inflammatory Reflex for the Treatment of Inflammation-Mediated Diseases. [2022]Treating diseases nonpharmacologically, using targeted neurostimulation instead of systemic drugs, is a hallmark of the burgeoning field of bioelectronic medicine. In this review, we provide a brief overview of the discovery and function of the prototypical neuroimmune reflex, the "inflammatory reflex." We discuss various biomarkers developed and used to translate early physiological discoveries into dosing parameters used in experimental settings, from the treatment of animal models of disease through a proof-of-concept clinical study in rheumatoid arthritis (RA). Finally, we relate how unique aspects of this form of therapy enabled the design of a next-generation implanted pulse generator using integrated electrodes, currently under evaluation in a U.S.-based clinical study for patients with drug refractory RA.
Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear. [2022]Rheumatoid arthritis (RA) is a chronic and debilitating inflammatory disease characterized by extensive joint tissue inflammation. Implantable bioelectronic devices targeting the inflammatory reflex reduce TNF production and inflammation in preclinical models of inflammatory disease, and in patients with RA and Crohn's disease. Here, we assessed the effect of applying a vibrotactile device to the cymba concha of the external ear on inflammatory responses in healthy subjects, as well as its effect on disease activity in RA patients.
Vagus nerve stimulation in musculoskeletal diseases. [2021]The vagus nerve is the main nerve of the parasympathetic autonomic nervous system. Beyond its vegetative functions, the vagus nerve possesses anti-inflammatory and analgesic properties. Initially developed in the treatment of refractory epilepsy, vagus nerve stimulation (VNS) is currently being evaluated in several musculoskeletal diseases. VNS can be invasive by placing an electrode around the cervical vagus nerve and connected to a generator implanted subcutaneously or non-invasive stimulating the cervical vagus nerve branch percutaneously (auricular or cervical). In rheumatoid arthritis (RA) patients, VNS has been shown to dampen the inflammatory response of circulatory peripheral cells. Several open-labeled small pilot studies have demonstrated that VNS, either invasive or transcutaneous, is associated with a significant decrease of RA disease activity. As well, other studies have shown that VNS could limit fatigue in Sjogren's syndrome and systemic lupus, or decrease pain in fibromyalgia as well as in erosive hand osteoarthritis. However, some questions remain, such as the settings of stimulation, the duration of treatment, or the optimal stimulation route. Finally, randomized controlled trials versus sham stimulation with large samples of patients are mandatory to definitively conclude about the efficacy of VNS.
pH-responsive dual pulse multiparticulate dosage form for treatment of rheumatoid arthritis. [2013]Dual pulse multiparticulate systems may provide relief from circadian disorder rheumatoid arthritis.