Clinical trial NCT05710640: Transcutaneous Vagus Nerve Stimulation (tcVNS) in JIA
Official title: Using the Cholinergic Anti-Inflammatory Pathway to Treat Juvenile Idiopathic Arthritis (AJA01)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Juvenile Idiopathic Arthritis (JIA)
Keywords: Juvenile Idiopathic Arthritis
JIA
Children
tcVNS
Cytokines
Inflammation
Nonsignificant risk
NSR
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Autoimmunity Centers of Excellence (ACE)
name: Northwell Health
First posted: 2023-02-02
Enrollment: 18
Sex: ALL
Minimum age (years): 5
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Participant is 5 through 18 years of age (inclusive) at screening.
2. Regarding informed consent and compliance:

   1. 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.
   2. 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.
   3. If 18 years of age, the participant is willing and able to understand and provide informed consent and comply with study protocol.
3. 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:

   1. rheumatoid-factor negative polyarthritis
   2. rheumatoid-factor positive polyarthritis
   3. persistent oligoarthritis
   4. extended oligoarthritis
   5. psoriatic arthritis
   6. enthesitis-related arthritis
   7. systemic arthritis
4. The participant has \>=3 joints with active arthritis at screening
5. 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 2 weeks prior to screening: i. NSAIDs

   c. 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

   d. stable dose for at least 12 weeks prior to screening: i. abatacept
6. If a female of child-bearing potential, the participant has a negative urine pregnancy test at screening
7. If of reproductive potential, must agree to abstinence or effective methods of birth control for the duration of the study

Exclusion Criteria:

1. Other than NSAIDs or intra-articular injections, participant has been treated for JIA with lack of efficacy with:

   1. More than 2 different classes of therapies, or
   2. More than 3 medications in total
2. Participant has received high-dose steroids (\>=0.2 mg/kg/day) within the 28 days prior to screening.
3. 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:

   1. Ferritin \>1000 ng/mL
   2. White blood cell (WBC) ≥15,000/mm\^3
4. Participant has had an active acute systemic infection within 2 weeks of screening. involving fever (100.4⁰F or higher) for more than 24 hours, requirement for systemic antibiotics or antivirals, GI symptoms lasting 48 hours or more, or the need to hold second line medications for JIA (methotrexate or biologic).
5. Participant has a history of arrhythmia.
6. Participant has been diagnosed with postural orthostatic tachycardia syndrome (POTS).
7. Participant has received an intra-articular cortisone injection within the 28 days prior to screening.
8. 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.
9. Participant has received chronic treatment with an anti-cholinergic medication, including over the counter medications.
10. Participant has received treatment with rituximab:

    1. Within one year of screening
    2. At any time previously without documented B cell repletion
11. Participant has a comorbid disease that has required treatment with corticosteroids within the past year.
12. Participant has an implantable electronic device such as a pacemaker, defibrillator, hearing aid, cochlear implant, insulin pump or deep brain stimulator.
13. Participant has used cutaneous vagus nerve stimulation within 12 weeks prior to screening.
14. Participant has received a live attenuated viral vaccine within 28 days prior to screening or is expected to receive one during the study.
15. Participant has any condition which, in the opinion of the investigator, would jeopardize the participant's safety following exposure to a study intervention.
16. 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.

Primary outcomes:
measure: The proportion of participants achieving >= 50 percent improvement in clinical status as defined by JIA ACR 50
timeFrame: At Week 8
Secondary outcomes:
measure: Day 0 as the baseline: The proportion of participants achieving a JIA ACR 50 response
timeFrame: At Weeks 4, 12, and 16
measure: Day 0 as the baseline: The proportion of participants achieving a JIA ACR 30 response
timeFrame: At Weeks 4, 8, 12, and 16
measure: Day 0 as the baseline: The proportion of participants achieving a JIA ACR 70 response
timeFrame: At Weeks 4, 8, 12, and 16
measure: Day 0 as the baseline: The change in Juvenile Disease Activity Score-27 (JADAS-27)
timeFrame: At Weeks 4, 8, 12, and 16
measure: Week 8 as the baseline: The proportion of participants achieving a JIA ACR 50 response
timeFrame: At Weeks 12 and 16
measure: Week 8 as the baseline: The proportion of participants achieving a JIA ACR 30 response
timeFrame: At Weeks 12 and 16
measure: Week 8 as the baseline: The proportion of participants achieving a JIA ACR 70 response
timeFrame: At Weeks 12 and 16
measure: Week 8 as the baseline: The change in Juvenile Disease Activity Score-27 (JADAS-27)
timeFrame: At Weeks 12, and 16
measure: Longitudinal trends in Juvenile Arthritis Disease Activity Score-27 (JADAS-27)
timeFrame: From Day 0 to Week 16
measure: Incidence of Adverse Events (AEs) and Severe Adverse Events (SAEs)
timeFrame: From Day 0 to Week 16
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Orlando
country: United States
facility: Nemours Children's Health: Department of Pediatric Rheumatology
state: Florida
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Lake Success
country: United States
facility: Cohen Children's Medical Center, Northwell Health
state: New York
city: New York
country: United States
facility: Stephen D. Hassenfield Children's Center at NYU Langone Health
state: New York
city: Salt Lake City
country: United States
facility: Division of Pediatric Rheumatology at the University of Utah School of Medicine and Primary Children's Hospital
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: Feinstein Institutes for Medical Research, Cohen Children's Medical Center: Pediatric Rheumatology
name: Beth Gottlieb
role: STUDY_CHAIR
affiliation: Northwell Health
name: Cynthia Aranow, MD
role: STUDY_CHAIR
affiliation: Northwell Health
name: Timir Datta-Chaudhuri, PhD
role: STUDY_CHAIR
affiliation: Northwell Health
name: Betty Diamond, MD
role: STUDY_CHAIR
References: