Splenic Stimulation for RA

Study Overview
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Brief Summary
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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.

Detailed Description
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Participants with active rheumatoid arthritis (RA) who receive the implantable system will be randomly assigned to receive either active stimulation or sham-stimulation for 12 weeks (Period 1). Following Period 1, all participants will enter an open label phase (Period 2) during which participants who responded to stimulation will continue on stimulation; whereas participants who received sham stimulation, or were stimulation non-responders, will receive a market-approved RA drug for 12 weeks. At the end of Period 2, participants who respond to their Period 2 therapy but still exhibit signs and symptoms of RA will enter the Treat-to-target period (Period 3); others will proceed to Period 4 (Long-term Follow-up). During the Treat-to-Target period, participants will be treated with dual therapy (stimulation in combination with the market-approved RA drug) for up to 24 weeks. Period 4 provides long term safety follow up for all study participants for a period of 5 years. Participants may receive stimulation in combination with other approved and standard of care therapies, subject to a favorable benefit-risk assessment in the judgement of the treating rheumatologist.

Official Title
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Multipart Exploratory Study to Evaluate Splenic Nerve Stimulation in Patients With Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Device: Active Stimulation
* Device: Sham Stimulation
* Drug: Baricitinib
* Drug: Background Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult-onset RA of at least six months duration Male or female participants, 22-75 years of age Active RA Inadequate Response to at least 2 biologic DMARDs and/or JAK-inhibitors (JAKis) including at least one TNF inhibitor. Have an appropriate washout from previously used biological DMARDs or JAKi Receiving treatment with standard dose(s) of conventional synthetic DMARD(s) Exclusion Criteria: Inability to provide informed consent Significant psychiatric disease or substance abuse History of unilateral or bilateral vagotomy Active or latent tuberculosis Known infection with human immunodeficiency virus (HIV); current acute or chronic hepatitis B or hepatitis C; previous hepatitis B Positive SARS COV 2 PCR screening test for COVID-19 infection (at the point of screening for this study) Currently implanted electrically active medical devices (e.g., cardiac pacemakers, automatic implantable cardioverter-defibrillators) Previous splenectomy

Ages Eligible for Study
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Minimum Age: 22 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Multicenter study with 4 periods. Period 1 is a randomized, controlled double-blind period where participants are assigned randomly to either active or sham stimulation. During the open-label Periods 2 through 4, participants are assigned treatment based on responses to treatments in the prior period
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Stimulation; Period 1<br>Active stimulation for 12 weeks in addition to stable dose of csDMARD therapy. | Device: Active Stimulation<br>* Stimulation will be turned ON and applied during each day of the period.<br>Drug: Background Treatment<br>* Stable dose of standard background treatment (e.g., csDMARD therapy)<br>|
| Sham Comparator: Sham Stimulation; Period 1<br>Sham stimulation for 12 weeks in addition to stable dose of csDMARD therapy. | Device: Sham Stimulation<br>* Sham stimulation will be provided during the period<br>Drug: Background Treatment<br>* Stable dose of standard background treatment (e.g., csDMARD therapy)<br>|
| Experimental: Open label active stimulation, Period 2<br>Open label active stimulation for 12 additional weeks in addition to stable dose of csDMARD therapy. | Device: Active Stimulation<br>* Stimulation will be turned ON and applied during each day of the period.<br>Drug: Background Treatment<br>* Stable dose of standard background treatment (e.g., csDMARD therapy)<br>|
| Other: Open label RA Drug, Period 2<br>Open label drug treatment with baricitinib for 12 weeks in addition to stable dose of csDMARD therapy. | Drug: Baricitinib<br>* Baricitinib (2 mg) is administered daily during the period.<br>Drug: Background Treatment<br>* Stable dose of standard background treatment (e.g., csDMARD therapy)<br>|
| Experimental: RA drug combined with active stimulation, Period 3<br>Participants on baricitinib during Period 2 will have active stimulation added for 24 weeks. Participants will also receive a stable dose of csDMARD therapy. | Device: Active Stimulation<br>* Stimulation will be turned ON and applied during each day of the period.<br>Drug: Baricitinib<br>* Baricitinib (2 mg) is administered daily during the period.<br>Drug: Background Treatment<br>* Stable dose of standard background treatment (e.g., csDMARD therapy)<br>|
| Experimental: Active stimulation combined with RA drug, Period 3<br>Participants on active stimulation during Period 2 will have baricitinib added for 24 weeks. Participants will also receive a stable dose of csDMARD therapy. | Device: Active Stimulation<br>* Stimulation will be turned ON and applied during each day of the period.<br>Drug: Baricitinib<br>* Baricitinib (2 mg) is administered daily during the period.<br>Drug: Background Treatment<br>* Stable dose of standard background treatment (e.g., csDMARD therapy)<br>|
| Other: Long-term Follow-up, Period 4<br>Standard of care treatments with or without stimulation | Device: Active Stimulation<br>* Stimulation will be turned ON and applied during each day of the period.<br>Drug: Background Treatment<br>* Stable dose of standard background treatment (e.g., csDMARD therapy)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events [Safety and Tolerability] | Adverse Events (AEs) may include clinically significant findings from Laboratory Safety Assessments (clinical chemistry and hematology), vital signs (blood pressure, heart rate, respiratory rate, and body temperature), and 12-Lead EKG | Up through the end of Period 1 (Period 1 is up to 12 weeks duration) | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] |  | During Period 2 (Period 2 is up to 12 weeks in duration beyond Period 1) | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] |  | During Period 3 (Period 3 is up to 24 weeks in duration beyond Period 2) | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] |  | During Period 4 (Period 4 is up to 5 years in duration beyond Period 3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the 28 Joint Disease Activity Score 28 - C reactive protein (DAS28-CRP) |  | Baseline to 12 weeks (Period 1) | 
| Change in the level of Lipopolysaccharide (LPS)-inducible release of Tumor Necrosis Factor (TNFα) in whole blood assay |  | Baseline to 12 weeks (Period 1) | 
| Change in the level of LPS-inducible release of TNFα in whole blood assay |  | Baseline to 24 weeks (Period 2) | 
| Change in the level of LPS-inducible release of Interleukin 6 (IL-6) in whole blood assay |  | Baseline to 12 weeks (Period 1) | 
| Change in the level of LPS-inducible release of Interleukin 6 (IL-6) in whole blood assay |  | Baseline to 24 weeks (Period 2) | 
| Change in the level of LPS-inducible release of IL-8 in whole blood assay |  | Baseline to 12 weeks (Period 1) | 
| Change in the level of LPS-inducible release of IL-8 in whole blood assay |  | Baseline to 24 weeks (Period 2) | 
| Change in the level of LPS-inducible release of IL-17 in whole blood assay |  | Baseline to 12 weeks (Period 1) | 
| Change in the level of LPS-inducible release of IL-17 in whole blood assay |  | Baseline to 24 weeks (Period 2) | 
| Change in DAS28-CRP |  | Baseline to 24 weeks (Period 2) | 
| Change in DAS28-CRP |  | Baseline to 36 weeks (Period 3) | 
| Change in DAS28-CRP |  | Baseline to 48 weeks (Period 3) | 
| Change in Health Assessment Questionnaire Disability Index (HAQ-DI) score |  | Baseline to 12 weeks (Period 1) | 
| Change in HAQ-DI score |  | Baseline to 24 weeks (Period 2) | 
| Change in HAQ-DI score |  | Baseline to 36 weeks (Period 3) | 
| Change in HAQ-DI score |  | Baseline to 48 weeks (Period 3) | 
| Change in Short Form 36 (SF-36) physical component score |  | Baseline to 12 weeks (Period 1) | 
| Change in SF-36 physical component score |  | Baseline to 24 weeks (Period 2) | 
| Change in SF-36 physical component score |  | Baseline to 36 weeks (Period 3) | 
| Change in SF-36 physical component score |  | Baseline to 48 weeks (Period 3) | 
| Change in SF-36 mental component score |  | Baseline to 12 weeks (Period 1) | 
| Change in SF-36 mental component score |  | Baseline to 24 weeks (Period 2) | 
| Change in SF-36 mental component score |  | Baseline to 36 weeks (Period 3) | 
| Change in SF-36 mental component score |  | Baseline to 48 weeks (Period 3) | 
| Change in SF-36 domain score |  | Baseline to 12 weeks (Period 1) | 
| Change in SF-36 domain score |  | Baseline to 24 weeks (Period 2) | 
| Change in SF-36 domain score |  | Baseline to 36 weeks (Period 3) | 
| Change in SF-36 domain score |  | Baseline to 48 weeks (Period 3) | 
| To evaluate the usability of the external Galvani System devices and accessories | Summarize feedback collected on a questionnaire pertaining to the use of the external Galvani System devices | Through 48 weeks | 
| To evaluate the participants' perception of therapy and sensation | A form is provided to participants at each visit after randomization to describe any sensations that may be associated with the Galvani System | Through 48 weeks | 
| Evaluate device performance as assessed by tabulation of device deficiencies |  | Through 48 weeks | 
| Change in DAS28-CRP in participants who remain on active stimulation during Period 2 |  | week 12 to week 24 | 
| Incidence of participants who remain on active stimulation achieving DAS28-CRP score <2.6 at the end of Period 2 |  | Time Frame: Week 24 | 
| Change in DAS28-CRP in participants who are given Drug treatment with baricitinib during Period 2 |  | week 12 to week 24 | 
| Incidence of a change in DAS28-CRP greater than 1.2 units in participants who are given Drug treatment with baricitinib during Period 2 |  | week 12 to week 24 | 
| Incidence of participants who are given drug treatment with baricitinib achieving DAS28-CRP score <2.6 at the end of Period 2 |  | Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Electrical stimulation, random allocation, inflammation, active implantable medical device, Laparoscopy, antirheumatic agents, autonomic nervous system, feasibility studies