Transcutaneous Vagus Nerve Stimulation (tcVNS) in JIA (AJA01)

• ClinicalTrials.gov Identifier: NCT05710640
• Recruitment Status: Recruiting
• First Posted: February 2, 2023
• Last Update Posted: April 15, 2024
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Autoimmunity Centers of Excellence (ACE); Feinstein Institute for Medical Research (FIMR)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Juvenile Idiopathic Arthritis (JIA)	Device: Active tcVNS or Sham tcVNS; Device: Active tcVNS	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Using the Cholinergic Anti-Inflammatory Pathway to Treat Juvenile Idiopathic Arthritis (AJA01)
• Actual Study Start Date: June 27, 2023
• Estimated Primary Completion Date: August 1, 2025
• Estimated Study Completion Date: August 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Blinded phase; Participants will receive 5 minutes of active tcVNS or sham tcVNS daily for 8 weeks.	Device: Active tcVNS or Sham tcVNS; 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.; Other Name: tVNS
Experimental: Open-Label phase; 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; 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.; Other Name: tVNS

Outcome Measures

Primary Outcome Measures :

1. The proportion of participants achieving >= 50 percent improvement in clinical status as defined by JIA ACR 50 [ Time Frame: At Week 8 ]

   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:

   1. number of joints with active arthritis
   2. number of joints with limited motion
   3. physician's assessment of disease activity (measured on a 10 cm visual analog scale)
   4. parent/patient assessment of overall well-being (measured on a 10 cm visual analog scale)
   5. a validated measure of physical function Childhood Health Assessment Questionnaire (CHAQ)
   6. 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

Secondary Outcome Measures :

1. Day 0 as the baseline: The proportion of participants achieving a JIA ACR 50 response [ Time Frame: At Weeks 4, 12, and 16 ]
2. Day 0 as the baseline: The proportion of participants achieving a JIA ACR 30 response [ Time Frame: At Weeks 4, 8, 12, and 16 ]
3. Day 0 as the baseline: The proportion of participants achieving a JIA ACR 70 response [ Time Frame: At Weeks 4, 8, 12, and 16 ]
4. Day 0 as the baseline: The change in Juvenile Disease Activity Score-27 (JADAS-27) [ Time Frame: At Weeks 4, 8, 12, and 16 ]
   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.
5. Week 8 as the baseline: The proportion of participants achieving a JIA ACR 50 response [ Time Frame: At Weeks 12 and 16 ]
6. Week 8 as the baseline: The proportion of participants achieving a JIA ACR 30 response [ Time Frame: At Weeks 12 and 16 ]
7. Week 8 as the baseline: The proportion of participants achieving a JIA ACR 70 response [ Time Frame: At Weeks 12 and 16 ]
8. Week 8 as the baseline: The change in Juvenile Disease Activity Score-27 (JADAS-27) [ Time Frame: At Weeks 12, and 16 ]
   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.
9. Longitudinal trends in Juvenile Arthritis Disease Activity Score-27 (JADAS-27) [ Time Frame: From Day 0 to Week 16 ]
   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.
10. Incidence of Adverse Events (AEs) and Severe Adverse Events (SAEs) [ Time Frame: From Day 0 to Week 16 ]

Eligibility Criteria

• Ages Eligible for Study: 5 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

University of California San Francisco; Recruiting

San Francisco, California, United States, 94158

Contact: Zilan Zheng 415-353-1301 zilan.zheng@ucsf.edu

Principal Investigator: Susan Kim, MD

United States, Florida

Nemours Children's Health: Department of Pediatric Rheumatology; Not yet recruiting

Orlando, Florida, United States, 32827

Principal Investigator: Mary Toth, MD

United States, Georgia

Emory University, Children's Healthcare of Atlanta- Center for Advanced Pediatrics: Division of Rheumatology; Recruiting

Atlanta, Georgia, United States, 30329

Contact: Sampath Prahalad, MD 404-785-5437 sprahal@emory.edu

Principal Investigator: Sampath Prahalad, MD

United States, Illinois

University of Chicago, Comer Children's Hospital; Not yet recruiting

Chicago, Illinois, United States, 60637

Principal Investigator: Melissa Tesher, MD

United States, Indiana

Indiana University; Recruiting

Indianapolis, Indiana, United States, 46202

Contact: Amy Rakestraw 317-274-2172 arakestr@iu.edu

Principal Investigator: Stacey Tarvin, MD

United States, New York

Cohen Children's Medical Center, Northwell Health; Recruiting

Lake Success, New York, United States, 11040

Contact: Ashley Machado 516-472-3711 amachado3@northwell.edu

Principal Investigator: Beth Gottlieb, MD

Stephen D. Hassenfield Children's Center at NYU Langone Health; Recruiting

New York, New York, United States, 10016

Contact: Thomas Chalothron 646-501-7384 Thomas.Chalothron@nyulangone.org

Principal Investigator: Philip Kahn

Hospital for Special Surgery; Recruiting

New York, New York, United States, 10021

Contact: Julia Klauss 212-774-2703 klaussj@HSS.EDU

Principal Investigator: Karen Onel, MD

United States, Pennsylvania

University of Pittsburgh; Recruiting

Pittsburgh, Pennsylvania, United States, 15224

Contact: Vibha Chauhan 412-692-7924 vibha.chauhan@chp.edu

Principal Investigator: Margalit Rosenkranz, MD

United States, Utah

Division of Pediatric Rheumatology at the University of Utah School of Medicine and Primary Children's Hospital; Recruiting

Salt Lake City, Utah, United States, 84132

Contact: Suzy Richins 801-585-5067 Suzy.Richins@hsc.utah.edu

Principal Investigator: Aimee Hersh, M.D

United States, Washington

Seattle Children's Hospital; Recruiting

Seattle, Washington, United States, 98105

Contact: Nidhi Naik 206-987-5149 Nidhi.Naik@seattlechildrens.org

Principal Investigator: Esi Morgan, MD

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Autoimmunity Centers of Excellence (ACE)

Feinstein Institute for Medical Research (FIMR)

Investigators

• Study Chair: Beth Gottlieb; Feinstein Institutes for Medical Research, Cohen Children's Medical Center: Pediatric Rheumatology
• Study Chair: Cynthia Aranow, MD; Feinstein Institutes for Medical Research
• Study Chair: Timir Datta-Chaudhuri, PhD; Feinstein Institutes for Medical Research
• Study Chair: Betty Diamond, MD; Feinstein Institutes for Medical Research

More Information

Additional Information:

Autoimmunity Centers of Excellence (ACE) 

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT05710640
• Other Study ID Numbers: DAIT AJA01
• First Posted: February 2, 2023
• Last Update Posted: April 15, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The plan is to share data upon completion of the study in the Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from the Division of Allergy Immunology and Transplantation-funded grants and contracts.
• Time Frame: On average, within 24 months after database lock for the trial.
• Access Criteria: Open access.
• URL: https://www.immport.org/home

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Juvenile Idiopathic Arthritis; JIA; Children; tcVNS; Cytokines; Inflammation; Nonsignificant risk; NSR

Additional relevant MeSH terms:

Arthritis; Arthritis, Juvenile; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases