Transcutaneous VNS to Treat Pediatric IBD

Not Applicable

Completed

• Conditions: Ulcerative Colitis; Crohn Disease
• Interventions: Device: Transcutaneous Electrical Nerve Stimulation (TENS)

• Registration Number: NCT03863704
• Lead Sponsor: Northwell Health

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2019-02-14
• Study First Submitted: 2019-02-14
• Study First Submitted QC: 2019-03-04
• Study First Posted: 2019-03-05
• Primary Completion: 2022-12-31
• Study Completion: 2023-12-31
• Status Verified: 2024-09
• Last Update Submitted: 2024-09-30
• Last Update Posted: 2024-10-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

1. Age 10-21 years

2. IBD diagnosis for at least 3 months, confirmed by clinical, biochemical, and endoscopic evaluations

3. Elevated Fecal calprotectin ≥ 200 ug/g within the past 4 weeks prior to enrollment

4. Evidence of active inflammatory disease despite treatment with at least one conventional therapy

5. If on corticosteroids, the dose must be stable and ≤ 10mg/day (prednisone or equivalent) for at least 14 days before entry into study

6. 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

7. 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

8. Able and willing to give written informed consent and comply with the requirements of the study protocol.

Exclusion Criteria

1. Expectation to increase corticosteroids and/or immunosuppressive treatment
2. Presence of bowel stricture with prestenotic dilatation
3. Presence of intra-abdominal or perirectal abscess
4. Pediatric UC activity Index (PUCAI) score ≥ 65 (severe)
5. weighted Pediatric Crohn Disease Activity Index (wPCDAI) score > 57.5 (severe)
6. Active treatment with antibiotics
7. Presence of active intestinal infection or documented infection by stool PCR or culture analysis in the previous 6 weeks
8. Continuous treatment with an anti-cholinergic medication, including over the counter medications
9. Implantable electronic devices such as pacemakers, defibrillators, hearing aids, cochlear implants or deep brain stimulators.
10. Current tobacco or nicotine user (to limit potential confounding effects of exposure to nicotine)
11. 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
12. Any planned surgical procedure requiring general anesthesia within the course of the study
13. Participation in any other Investigational drug and/or treatment currently or planned during the length of the study
14. Any condition which, in the opinion of the investigator, would jeopardize the subject's safety following exposure to a study intervention
15. Pregnancy or Lactation
16. Comorbid disease with high likelihood of requiring corticosteroid use
17. Inability to comply with study and follow-up procedures
18. Non-English speaking
19. Known cardiac condition causing or with potential to cause arrhythmia

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
nerve stimulation ear then leg	Transcutaneous Electrical Nerve Stimulation (TENS)	Subjects in this arm will be randomized to receive nerve stimulation with TENS of the ear followed by leg stimulation
nerve stimulation leg then ear	Transcutaneous Electrical Nerve Stimulation (TENS)	Subjects in this arm will be randomized to receive leg nerve stimulation with TENS followed by ear nerve stimulation
Subjects receiving Infliximab	Transcutaneous Electrical Nerve Stimulation (TENS)	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.

Primary Outcome Measures

Name	Time	Method
Fecal Calprotectin	16 weeks	Change in fecal calprotectin over time

Secondary Outcome Measures

Name	Time	Method
Pediatric Ulcerative colitis activity index (PUCAI)	16 weeks	Change in Pediatric ulcerative colitis activity index over time
Patient Reported Outcome (PRO)	16 weeks	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
Physician Global Assessment (PGA) Score	16 weeks	Change in physician global assessment score over time
Weighted Pediatric Crohn Disease activity index (wPCDAI)	16 weeks	Change in weighted Pediatric Crohn Disease activity index over time
Heart Rate Variability (HRV)	16 weeks	Evaluating change in HRV from baseline until study completion
Change in Whole blood stimulated cytokine levels over time	16 weeks	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

Trial Locations

Locations (1)

Steven & Alexandra Cohen Children's Medical Center of New York; 🇺🇸 New Hyde Park, New York, United States