Transcutaneous Vagus Nerve Stimulation (tcVNS) in JIA

Study Overview
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Brief Summary
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The study is a multicenter, double-blind, sham-controlled trial to evaluate the safety and effectiveness of tcVNS on pain and inflammation associated with JIA. tcVNS is administered with a device that gives off mild electrical impulses through the skin to stimulate the vagus nerve. Part of the vagus nerve and its branches are located in the head and neck. For this study, the impulses will be administered in areas overlying the vagus nerve using a small electrode. The electrode helps to conduct the stimulation through the skin. This stimulation triggers a chemical response through the nerves and has been found to be effective in reducing pain and inflammation in several diseases. The primary objective of this study is to determine the effect of tcVNS on JIA ACR 50 in participants with active JIA. The components of the active and sham tcVNS devices, utilizing the Roscoe Medical TENS 7000, have been FDA 510(k)-cleared and have been determined by the IRB to be a nonsignificant risk device.

Detailed Description
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AJA01 is a multicenter, double-blind, sham-controlled, 16-week trial to evaluate the safety and effectiveness of tcVNS for the treatment of JIA. A total of 100 participants will be randomized 1:1 to treatment with active tcVNS or sham tcVNS for 5 minutes once a day for 8 weeks. During this time, participants/parents, and participant assessors will be blinded to treatment assignment; treatments on clinic visit days will be conducted in the clinic under the supervision of a trained, unblinded staff member, and participants will only discuss the stimulation procedure with this staff member. An unblinded site investigator will follow up on any safety events. The double-blind, sham-controlled 8-week period will be followed by an 8-week open-label period in which all participants will receive treatment with active tcVNS once a day for 5 minutes. Participants and their parents will be told it is likely they will feel the stimulation, but it should not be painful. There are 10 visits for the study, 8 clinic visits and 2 tele-visits. Participants will have physical exams with joint assessments, lab tests, and questionnaire completion by the physicians and participants at each clinic visit. Participants will be trained by the unblinded coordinator to perform stimulation during the clinic visit following the randomization. Participants will perform the stimulation at home for 5 minutes daily. Participants will complete a diary to document the daily stimulation.

Official Title
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Using the Cholinergic Anti-Inflammatory Pathway to Treat Juvenile Idiopathic Arthritis (AJA01)

Conditions
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Juvenile Idiopathic Arthritis (JIA)

Intervention / Treatment
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* Device: Active tcVNS or Sham tcVNS
* Device: Active tcVNS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is 5 through 18 years of age (inclusive) at screening. Regarding informed consent and compliance: If 5 through 6 years of age, the participant's guardian is willing and able to understand and provide informed consent and comply with study protocol. If 7 through 17 years of age, the participant is willing and able to sign assent and comply with study protocol, and the participant's guardian is willing and able to understand and provide informed consent and comply with study protocol. If 18 years of age, the participant is willing and able to understand and provide informed consent and comply with study protocol. The participant has a Juvenile Idiopathic Arthritis (JIA) diagnosis meeting International League of Associations for Rheumatology (ILAR) classification criteria with one of the following subtypes: rheumatoid-factor negative polyarthritis rheumatoid-factor positive polyarthritis persistent oligoarthritis extended oligoarthritis psoriatic arthritis enthesitis-related arthritis systemic arthritis The participant has >=3 joints with active arthritis at screening If the participant is receiving therapy for JIA at screening, that therapy is stable for the time period outlined below and is expected to remain stable for the duration of the study: a. stable dose for at least 1 week prior to screening: i. Oral steroids, <= 0.2 mg/kg/day with a maximum 10 mg/day dose b. stable dose for at least 8 weeks prior to screening i. adalimumab ii. anakinra iii. canakinumab iv. certolizumab pegol v. etanercept vi. golimumab vii. infliximab viii. leflunomide ix. methotrexate x. tocilizumab c. stable dose for at least 12 weeks prior to screening: i. abatacept If a female of child-bearing potential, the participant has a negative urine pregnancy test at screening If of reproductive potential, must agree to abstinence or effective methods of birth control for the duration of the study Exclusion Criteria: Participant has been treated for JIA with more than 2 therapies, other than NSAIDs or intra-articular injections, with lack of efficacy. Participant has received high-dose steroids (>=0.2 mg/kg/day) within the 28 days prior to screening. Participant has had active systemic disease (fever, systemic rash) within the 3 months prior to screening including any of the following lab manifestations at screening: Ferritin >1000 ng/mL White blood cell (WBC) ≥15,000/mm^3 Participant has had an active acute infection within 2 weeks of screening. Participant has a history of arrhythmia. Participant has been diagnosed with postural orthostatic tachycardia syndrome (POTS). Participant has received an intra-articular cortisone injection within the 28 days prior to screening. Participant has received treatment with an investigational drug or device during the 28 days prior to screening or within five half-lives of the investigational drug prior to screening/baseline, whichever is the greater length of time. Participant has received chronic treatment with an anti-cholinergic medication, including over the counter medications. Participant has received treatment with rituximab: Within one year of screening At any time previously without documented B cell repletion Participant has a comorbid disease that has required treatment with corticosteroids within the past year. Participant has an implantable electronic device such as a pacemaker, defibrillator, hearing aid, cochlear implant, insulin pump or deep brain stimulator. Participant has used cutaneous vagus nerve stimulation within 12 weeks prior to screening. Participant has received a live attenuated viral vaccine within 28 days prior to screening or is expected to receive one during the study. Participant has any condition which, in the opinion of the investigator, would jeopardize the participant's safety following exposure to a study intervention. Participant has any past or current medical problems or findings from a physical examination or laboratory testing that are not listed above but which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or may impact the quality or interpretation of the data obtained from the study.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 18 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinded phase<br>Participants will receive 5 minutes of active tcVNS or sham tcVNS daily for 8 weeks. | Device: Active tcVNS or Sham tcVNS<br>* tcVNS is administered with a study device that gives off mild electrical impulses through the skin to stimulate the vagus nerve (a nerve that travels underneath the skin in your neck and head). This stimulation triggers a chemical response through the nerves and has been found to be effective in reducing pain and inflammation in several diseases.<br>* Other names: tVNS;|
| Experimental: Open-Label phase<br>Participants will receive 5 minutes of stimulation via the active tcVNS for 8 weeks after a double-blind, sham-controlled 8- week period. | Device: Active tcVNS<br>* tcVNS is administered with a study device that gives off mild electrical impulses through the skin to stimulate the vagus nerve (a nerve that travels underneath the skin in your neck and head). This stimulation triggers a chemical response through the nerves and has been found to be effective in reducing pain and inflammation in several diseases.<br>* Other names: tVNS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of participants achieving >= 50 percent improvement in clinical status as defined by JIA ACR 50 | This primary endpoint will be compared between the active tcVNS and Sham tcVNS treatment arms. The Juvenile Idiopathic Arthritis American College of Rheumatology (JIA ACR) 50 is a validated composite response consisting of 6 core criteria: number of joints with active arthritis number of joints with limited motion physician's assessment of disease activity (measured on a 10 cm visual analog scale) parent/patient assessment of overall well-being (measured on a 10 cm visual analog scale) a validated measure of physical function Childhood Health Assessment Questionnaire (CHAQ) a laboratory measure of inflammation c-Reactive Protein (CRP) The JIA ACR 50 is achieved if 3 of any 6 core set variables improve by at least 50 percent from baseline or Day 0 visit, and no more than 1 variable worsening by >30 percent | At Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Day 0 as the baseline: The proportion of participants achieving a JIA ACR 50 response |  | At Weeks 4, 12, and 16 | 
| Day 0 as the baseline: The proportion of participants achieving a JIA ACR 30 response |  | At Weeks 4, 8, 12, and 16 | 
| Day 0 as the baseline: The proportion of participants achieving a JIA ACR 70 response |  | At Weeks 4, 8, 12, and 16 | 
| Day 0 as the baseline: The change in Juvenile Disease Activity Score-27 (JADAS-27) | JADAS-27 is a validated composite disease activity measure for JIA. The JADAS-27 score was derived from four components; 1) Physician Global Assessment of Disease Activity (assessed on a VAS of 0 [no activity] to 10 [extreme activity]), 2) Parent/Patient Global Assessment (assessed on a VAS of 0 [very well] to 10 [very poor]), 3) Number of joints with active disease, 4) CRP (measured in milligram per liter [mg/L] and value normalized to 0 to 10 scale). The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity. | At Weeks 4, 8, 12, and 16 | 
| Week 8 as the baseline: The proportion of participants achieving a JIA ACR 50 response |  | At Weeks 12 and 16 | 
| Week 8 as the baseline: The proportion of participants achieving a JIA ACR 30 response |  | At Weeks 12 and 16 | 
| Week 8 as the baseline: The proportion of participants achieving a JIA ACR 70 response |  | At Weeks 12 and 16 | 
| Week 8 as the baseline: The change in Juvenile Disease Activity Score-27 (JADAS-27) | JADAS-27 is a validated composite disease activity measure for JIA. The JADAS-27 score was derived from four components; 1) Physician Global Assessment of Disease Activity (assessed on a VAS of 0 [no activity] to 10 [extreme activity]), 2) Parent/Patient Global Assessment (assessed on a VAS of 0 [very well] to 10 [very poor]), 3) Number of joints with active disease, 4) CRP (measured in milligram per liter [mg/L] and value normalized to 0 to 10 scale). The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity. | At Weeks 12, and 16 | 
| Longitudinal trends in Juvenile Arthritis Disease Activity Score-27 (JADAS-27) | JADAS-27 is a validated composite disease activity measure for JIA. The JADAS-27 score was derived from four components; 1) Physician Global Assessment of Disease Activity (assessed on a VAS of 0 [no activity] to 10 [extreme activity]), 2) Parent/Patient Global Assessment (assessed on a VAS of 0 [very well] to 10 [very poor]), 3) Number of joints with active disease, 4) CRP (measured in milligram per liter [mg/L] and value normalized to 0 to 10 scale). The overall JADAS-27 score ranges from 0-57. A higher score indicates more disease activity. | From Day 0 to Week 16 | 
| Incidence of Adverse Events (AEs) and Severe Adverse Events (SAEs) |  | From Day 0 to Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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JIA, Juvenile Idiopathic Arthritis, Children, tcVNS, Cytokines, Inflammation, Nonsignificant risk, NSR