Transcutaneous Cervical Vagus Nerve Stimulation (tcVNS) in JIA

Phase 2TerminatedNCT05710640

National Institute of Allergy and Infectious Diseases (NIAID)18 enrolled

Overview

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 using a small electrode at the cymba concha for participants receiving treatment with active tcVNS and at the neck for participants receiving sham stimulation. 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.

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 at the cymba concha or sham stimulation at the neck 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 at the cymba concha 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 Type

Interventions

Active tcVNSDEVICE

Participants being treated with an active tcVNS device will attach the stimulator, lead, and clip electrode to assemble the complete device and coat the electrode surfaces with electrode gel. The electrode will be placed on the cymba concha of a left ear that is free of earrings or other objects, cleaned internally and externally, and coated with a thin layer of electrode gel. The participant will gradually advance the stimulator knob clockwise until they feel the electrical stimulation at a level that is easily tolerated for 5 minutes and is not painful. The participant will apply the stimulation for 5 minutes, then the participant will turn off the stimulator, remove the electrode from the ear, and clean the ear and electrodes with gauze.

Sham tcVNSDEVICE

Participants being treated with a sham tcVNS device will place adhesive electrodes on the left side of the neck, which has had neck jewelry removed and has been cleaned at the site of treatment. The participant will then connect the lead to the electrodes and the stimulator to assemble the complete sham tcVNS device. The participant will gradually advance the stimulator knob clockwise until they feel the electrical stimulation at a level that is easily tolerated for 5 minutes and is not painful. Participants in this group will be instructed to not turn the knob above "3" on the dial as this is the maximum acceptable treatment level at the neck. The participant will apply the stimulation for 5 minutes, then the participant will turn off the stimulator, remove the electrode from the neck, and dispose of the electrodes.

Active tcVNSDEVICE

Eligibility

Sex: ALLMin age: 5 YearsMax age: 18 Years

Medical Language ↔ Plain English

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.

Locations (7)

University of California San Francisco School of Medicine: Department of Pediatrics, Division of Pediatric Rheumatology

San Francisco, California, United States

Nemours Children's Health: Department of Pediatric Rheumatology

Orlando, Florida, United States

Indiana University Medical Center: Riley Hospital for Children Department of Pediatric Rheumatology

Indianapolis, Indiana, United States

Feinstein Institutes for Medical Research, Cohen Children's Medical Center: Pediatric Rheumatology

Lake Success, New York, United States

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

New York, New York, United States

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

Salt Lake City, Utah, United States

Seattle Children's Hospital: Rheumatology Clinic

Seattle, Washington, United States

Outcomes

Primary Outcomes

Proportion of Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) 50 Responders at Week 8 Compared to Baseline

The 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 analogue scale (VAS)); parent/patient assessment of overall well-being (measured on a 10 cm VAS); a validated measure of physical function, Childhood Health Assessment Questionnaire (CHAQ); and a laboratory measure of inflammation, c-Reactive Protein (CRP). The JIA ACR 50 is achieved if 3 of any 6 core set variables improved by at least 50% from Baseline, and no more than 1 variable worsens by \>30%. A negative change from Baseline in any of the core set variables signifies improvement. Participants missing any of the JIA ACR core criteria at Week 8 are imputed as JIA ACR 50 non-responders at Week 8.

Time frame: Week 8

Secondary Outcomes

Proportion of Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) 50 Responders at Weeks 4, 12, and 16 Compared to Baseline

The 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 analogue scale (VAS)); parent/patient assessment of overall well-being (measured on a 10 cm VAS); a validated measure of physical function, Childhood Health Assessment Questionnaire (CHAQ); and a laboratory measure of inflammation, c-Reactive Protein (CRP). The JIA ACR 50 is achieved if 3 of any 6 core set variables improved by at least 50% from Baseline, and no more than 1 variable worsens by \>30%. A negative change from Baseline in any of the core set variables signifies improvement. Participants missing any of the JIA ACR core criteria at any visit are imputed as JIA ACR 50 non-responders at that visit.

Time frame: Weeks 4, 12, 16

Proportion of Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) 30 Responders at Weeks 4, 8, 12, and 16 Compared to Baseline

The JIA ACR 30 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 analogue scale (VAS)); parent/patient assessment of overall well-being (measured on a 10 cm VAS); a validated measure of physical function, Childhood Health Assessment Questionnaire (CHAQ); and a laboratory measure of inflammation, c-Reactive Protein (CRP). The JIA ACR 30 is achieved if 3 of any 6 core set variables improved by at least 30% from Baseline, and no more than 1 variable worsens by \>30%. A negative change from Baseline in any of the core set variables signifies improvement. Participants missing any of the JIA ACR core criteria at any visit are imputed as JIA ACR 30 non-responders at that visit.

Time frame: Weeks 4, 8, 12, 16

Proportion of Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) 70 Responders at Week 4, 8, 12, and 16 Compared to Baseline

The JIA ACR 70 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 analogue scale (VAS)); parent/patient assessment of overall well-being (measured on a 10 cm VAS); a validated measure of physical function, Childhood Health Assessment Questionnaire (CHAQ); and a laboratory measure of inflammation, c-Reactive Protein (CRP). The JIA ACR 70 is achieved if 3 of any 6 core set variables improved by at least 70% from Baseline, and no more than 1 variable worsens by \>30%. A negative change from Baseline in any of the core set variables signifies improvement. Participants missing any of the JIA ACR core criteria at any visit are imputed as JIA ACR 70 non-responders at that visit.

Time frame: Weeks 4, 8, 12, 16

Change From Baseline in Juvenile Arthritis Disease Activity Score in 27 Joints (JADAS-27) at Weeks 4, 8, 12, and 16

The JADAS-27 is a measurement of disease activity and is determined by adding the scores of its 4 components: physician's assessment of disease activity (measured on a 10 cm visual analogue scale (VAS)); parent/patient assessment of overall well-being (measured on a 10 cm VAS); number of joints with active arthritis; and a laboratory measure of inflammation, c-Reactive Protein (CRP), normalized to a value between 0 and 10. The JADAS-27 includes the following joints: cervical spine, elbows, wrists, metacarpophalangeal joints (from first to third), proximal inter-phalangeal joints, hips, knees, and ankles. This provides a score in the range of 0-57 with higher scores indicating worse disease activity. A negative change from Baseline signifies improvement.

Time frame: Baseline; Weeks 4, 8, 12, 16

Proportion of Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) 50 Responders at Weeks 12 and 16 Compared to Week 8

The 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 analogue scale (VAS)); parent/patient assessment of overall well-being (measured on a 10 cm VAS); a validated measure of physical function, Childhood Health Assessment Questionnaire (CHAQ); and a laboratory measure of inflammation, c-Reactive Protein (CRP). The JIA ACR 50 is achieved if 3 of any 6 core set variables improved by at least 50% from Week 8, and no more than 1 variable worsens by \>30%. A negative change from Week 8 in any of the core set variables signifies improvement. Participants missing any of the JIA ACR core criteria at any visit are imputed as JIA ACR 50 non-responders at that visit.

Time frame: Week 12 and 16

Proportion of Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) 30 Responders at Weeks 12 and 16 Compared to Week 8

The JIA ACR 30 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 analogue scale (VAS)); parent/patient assessment of overall well-being (measured on a 10 cm VAS); a validated measure of physical function, Childhood Health Assessment Questionnaire (CHAQ); and a laboratory measure of inflammation, c-Reactive Protein (CRP). The JIA ACR 30 is achieved if 3 of any 6 core set variables improved by at least 30% from Week 8, and no more than 1 variable worsens by \>30%. A negative change from Week 8 in any of the core set variables signifies improvement. Participants missing any of the JIA ACR core criteria at any visit are imputed as JIA ACR 30 non-responders at that visit.

Time frame: At Weeks 12 and 16

Proportion of Juvenile Idiopathic Arthritis (JIA) American College of Rheumatology (ACR) 70 Responders at Week 12 and 16 Compared to Week 8

The JIA ACR 70 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 analogue scale (VAS)); parent/patient assessment of overall well-being (measured on a 10 cm VAS); a validated measure of physical function, Childhood Health Assessment Questionnaire (CHAQ); and a laboratory measure of inflammation, c-Reactive Protein (CRP). The JIA ACR 70 is achieved if 3 of any 6 core set variables improved by at least 70% from Week 8, and no more than 1 variable worsens by \>30%. A negative change from Week 8 in any of the core set variables signifies improvement. Participants missing any of the JIA ACR core criteria at any visit are imputed as JIA ACR 70 non-responders at that visit.

Time frame: Weeks 12 and 16

Change From Week 8 in Juvenile Arthritis Disease Activity Score in 27 Joints (JADAS-27)

The JADAS-27 is a measurement of disease activity and is determined by adding the scores of its 4 components: physician's assessment of disease activity (measured on a 10 cm visual analogue scale (VAS)); parent/patient assessment of overall well-being (measured on a 10 cm VAS); number of joints with active arthritis; and a laboratory measure of inflammation, c-Reactive Protein (CRP) normalized to a value between 0-10. The JADAS-27 includes the following joints: cervical spine, elbows, wrists, metacarpophalangeal joints (from first to third), proximal inter-phalangeal joints, hips, knees, and ankles. This provides a score in the range of 0-57 with higher scores indicating worse disease activity. A negative change from Week 8 signifies improvement.

Time frame: Weeks 12 and 16

Longitudinal Trends From Baseline to Week 16 in Juvenile Arthritis Disease Activity Score in 27 Joints (JADAS-27)

The JADAS-27 is a measurement of disease activity and is determined by adding the scores of its 4 components: physician's assessment of disease activity (measured on a 10 cm visual analogue scale (VAS)); parent/patient assessment of overall well-being (measured on a 10 cm VAS); number of joints with active arthritis; and a laboratory measure of inflammation, c-Reactive Protein (CRP) normalized to a value between 0-10. The JADAS-27 includes the following joints: cervical spine, elbows, wrists, metacarpophalangeal joints (from first to third), proximal inter-phalangeal joints, hips, knees, and ankles. This provides a score in the range of 0-57 with higher scores indicating worse disease activity.

Time frame: Baseline; Weeks 4, 8, 12, 16

Number of Participants With a Treatment-emergent Adverse Event From Day 0 to Week 8.

A participant who experienced any of the following untoward or unfavorable medical occurrence(s) associated with the investigational device or any study mandated procedures following the first stimulation on Day 0 and prior to the Week 8 visit: * Grade 1 or higher mild palpitations, documented arrhythmia, or any unpleasant sensations caused by palpitations * Grade 1 or higher stimulation site reactions such as cutaneous irritation, pain, or skin burns * Grade 1 or higher Ear and labyrinth disorders as listed in the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, except those of the middle ear * Grade 1 or higher JIA flares * All other Grade 2 and higher AEs

Time frame: Day 0 to Week 8

Number of Participants With a Treatment-emergent Adverse Event From Week 8 to Week 16

A participant who experienced any of the following untoward or unfavorable medical occurrence(s) associated with the investigational device or any study mandated procedures between Week 8 and Week 16: * Grade 1 or higher mild palpitations, documented arrhythmia, or any unpleasant sensations caused by palpitations * Grade 1 or higher stimulation site reactions such as cutaneous irritation, pain, or skin burns * Grade 1 or higher Ear and labyrinth disorders as listed in the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, except those of the middle ear * Grade 1 or higher JIA flares * All other Grade 2 and higher AEs

Time frame: Week 8 to Week 16

Number of Participants With a Treatment-emergent Serious Adverse Event From Day 0 to Week 8

A participant who experienced any serious untoward or unfavorable medical occurrence(s) associated with the investigational device or any study mandated procedures following the first stimulation on Day 0 and prior to the Week 8 visit.