Transcutaneous VNS to Treat Pediatric IBD

Study Overview
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Brief Summary
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The current available therapies for inflammatory bowel disease (IBD), including immunomodulator and biologic medications may have toxicities limiting use or inadequate effect. We propose a novel approach to the treatment of IBD by using transcutaneous vagal nerve stimulation (VNS). Research has previously identified that VNS using a surgically implanted stimulator can improve symptoms and decrease inflammation in people with inflammatory diseases. This study will evaluate the use of non-invasive nerve stimulation through the skin (rather than through an implanted device) as a potential therapy in pediatric patients with Crohn Disease or ulcerative colitis. We will be evaluating how this nerve stimulation affects symptoms, markers of inflammation found in the blood and stool including cytokine levels, and heart rate variability. The primary hypothesis of the study is the use of transcutaneous VNS will decrease inflammation in people with IBD leading to improved signs and symptoms of disease. The primary endpoint of the study is to evaluate the change in fecal calprotectin after 16 weeks of nerve stimulation. Secondary endpoints include changes in symptom scores, blood cytokine levels, and heart rate variability.

Official Title
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Transcutaneous Vagal Nerve Stimulation to Treat Pediatric Inflammatory Bowel Disease

Conditions
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Crohn Disease, Ulcerative Colitis

Intervention / Treatment
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* Device: Transcutaneous Electrical Nerve Stimulation (TENS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 10-21 years IBD diagnosis for at least 3 months, confirmed by clinical, biochemical, and endoscopic evaluations Elevated Fecal calprotectin ≥ 200 ug/g within the past 4 weeks prior to enrollment Evidence of active inflammatory disease despite treatment with at least one conventional therapy If on corticosteroids, the dose must be stable and ≤ 10mg/day (prednisone or equivalent) for at least 14 days before entry into study If on 5-Aminosalicylate, dose must be stable with following parameters: 28 days on oral medication Prior to baseline calprotectin, 28 days on rectal medication or 2 weeks off rectal medication If on background immunosuppressive treatment the dose must be stable with the following parameters: 56 days (8 weeks) for Immunomodulators (methotrexate, 6-MP, Azathioprine) 112 days (16 weeks) for Infliximab, Adalimumab, Vedolizumab, Ustekinumab, other biologic Able and willing to give written informed consent and comply with the requirements of the study protocol. Exclusion Criteria: Expectation to increase corticosteroids and/or immunosuppressive treatment Presence of bowel stricture with prestenotic dilatation Presence of intra-abdominal or perirectal abscess Pediatric UC activity Index (PUCAI) score ≥ 65 (severe) weighted Pediatric Crohn Disease Activity Index (wPCDAI) score > 57.5 (severe) Active treatment with antibiotics Presence of active intestinal infection or documented infection by stool PCR or culture analysis in the previous 6 weeks Continuous treatment with an anti-cholinergic medication, including over the counter medications Implantable electronic devices such as pacemakers, defibrillators, hearing aids, cochlear implants or deep brain stimulators. Current tobacco or nicotine user (to limit potential confounding effects of exposure to nicotine) Bowel resection surgery within past 90 days prior to study enrollment and on no conventional IBD therapy, or planned surgery within the course of the study Any planned surgical procedure requiring general anesthesia within the course of the study Participation in any other Investigational drug and/or treatment currently or planned during the length of the study Any condition which, in the opinion of the investigator, would jeopardize the subject's safety following exposure to a study intervention Pregnancy or Lactation Comorbid disease with high likelihood of requiring corticosteroid use Inability to comply with study and follow-up procedures Non-English speaking Known cardiac condition causing or with potential to cause arrhythmia

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 21 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: nerve stimulation ear then leg<br>Subjects in this arm will be randomized to receive nerve stimulation with TENS of the ear followed by leg stimulation | Device: Transcutaneous Electrical Nerve Stimulation (TENS)<br>* To apply transcutaneous electrical stimulation using a TENS unit to the ear or the leg.<br>|
| Sham Comparator: nerve stimulation leg then ear<br>Subjects in this arm will be randomized to receive leg nerve stimulation with TENS followed by ear nerve stimulation | Device: Transcutaneous Electrical Nerve Stimulation (TENS)<br>* To apply transcutaneous electrical stimulation using a TENS unit to the ear or the leg.<br>|
| Other: Subjects receiving Infliximab<br>Subjects on Infliximab as part of their clinical care will not be randomized as the study treatment for these subjects will be the same. The sham arm is not included for patients on infliximab. | Device: Transcutaneous Electrical Nerve Stimulation (TENS)<br>* To apply transcutaneous electrical stimulation using a TENS unit to the ear or the leg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fecal Calprotectin | Change in fecal calprotectin over time | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Whole blood stimulated cytokine levels over time | Blood will be collected into 2 tubes, one with no stimulant and the other with lipopolysaccharide (LPS) to stimulate macrophages to produce cytokines. Cytokine levels within the blood will be assessed and compared to baseline levels. The cytokines being assayed include tumor necrosis factor-alpha, Interferon-gamma, Transforming Growth Factor-beta and Interleukins (IL) - 1, 6, 10, 12, 17, 18, 23. Samples will be collected for this analysis at week 0, 2, 4, and 24 | 16 weeks | 
| Patient Reported Outcome (PRO) | PROMIS Pediatric Profile v2.0-25 and PROMIS Parent Proxy v2.0- 25 questionnaires to evaluate the effect of VNS on abdominal pain intensity and interference in daily activities, fatigue, anxiety, depression, physical function and peer relationships | 16 weeks | 
| Pediatric Ulcerative colitis activity index (PUCAI) | Change in Pediatric ulcerative colitis activity index over time | 16 weeks | 
| Weighted Pediatric Crohn Disease activity index (wPCDAI) | Change in weighted Pediatric Crohn Disease activity index over time | 16 weeks | 
| Physician Global Assessment (PGA) Score | Change in physician global assessment score over time | 16 weeks | 
| Heart Rate Variability (HRV) | Evaluating change in HRV from baseline until study completion | 16 weeks |