A Study of Randomized Sham-control Auricular TENS Unit Stimulation in Pediatric Functional Gastrointestinal Disorders

Study Overview
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Brief Summary
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The purpose of this study is to see if using a micro-current through a device called a TENS (Transcutaneous Electrical Nerve Stimulator) unit helps to improve functional gastrointestinal disorder (FGID) symptoms in children by stimulation of the vagus nerve. The study will compare two methods of stimulation to determine if there is a difference in the two methods.

Official Title
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A Pilot Study of a Randomized Sham-control Auricular TENS Unit Stimulation to Improve Symptoms Through Vagal Modulation in Pediatric Functional Gastrointestinal Disorders

Conditions
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Functional Gastrointestinal Disorders, Vagus Nerve Autonomic Disorder, Irritable Bowel Syndrome, Nausea, Dyspepsia

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients 12-18 years old with chronic idiopathic nausea, function abdominal pain, dyspepsia and/or irritable bowel syndrome English Speaking Exclusion Criteria: Patients who are unable to stand upright during the heart rate variability recording Patients with a known bleeding disorder Gastric or cardiac pacer or defibrillator Poor circulation in lower limbs Swollen or inflamed outer ear Epilepsy Abdominal or inguinal hernia Any unstable medical condition, such as renal disease, uncontrolled diabetes, etc. Requires new medication during the 8 weeks of the study that may affect gastrointestinal symptoms, vagal modulation or immune response Inability to answer questionnaires or report pain on a 0-10 visual analog scale.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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Female

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
Interventional Model Description: 30 participants will be enrolled in this double-blind sham control study. Fifteen participants will undergo sham stimulation for 4 weeks followed by active microstimulation for 4 weeks. The other 15 participants will have active microstimulation for all 8 weeks.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Stimulation (8)<br>Participants will receive active auricular microstimulation via TENS unit for 8 weeks. Under guidance from the study team, participants will self-administer the TENS therapy for two 1-hour periods a day for 8 weeks. | Device: Transcutaneous Electrical Nerve Stimulation (TENS)<br>* Active Transcutaneous Auricular Microstimulation delivered by TENS device<br>* Other names: InTENSity Select Combo by Roscoe Medical;|
| Sham Comparator: Sham Stimulation (4), Active (4)<br>Participants will receive sham therapy via inactive TENS unit for 4 weeks, followed by active auricular microstimulation via TENS for 4 weeks. Under guidance from the study team, participants will self-administer the TENS therapy for two 1-hour periods a day for 8 weeks (4 weeks of therapy with inactive TENS, 4 weeks with active TENS). | Device: Transcutaneous Electrical Nerve Stimulation (TENS)<br>* Active Transcutaneous Auricular Microstimulation delivered by TENS device<br>* Other names: InTENSity Select Combo by Roscoe Medical;Device: Sham Transcutaneous Electrical Nerve Stimulation<br>* Sham therapy will be delivered by applying the TENS device with non-conductive electrodes so that no microstimulation is delivered<br>* Other names: InTENSity Select Combo by Roscoe Medical (Inactive);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Heart Rate Variability at 4 Weeks | EKG tracing will be used to analyze Heart Rate Variability as an indirect measure of vagal nerve output and central autonomic control. | Assessed at baseline, week 4, and week 8. Change in baseline to week 4 is reported. | 
| Change in Heart Rate Variability at 8 Weeks | EKG tracing will be used to analyze Heart Rate Variability as an indirect measure of vagal nerve output and central autonomic control. | Assessed at baseline, week 4, and week 8. Change in baseline to week 8 is reported. | 
| Change in Mitochondrial Bioenergetics Measured by Basal Oxygen Consumption Rate at 4 Weeks (Basal Consumption) | Blood draw will be tested for mitochondrial function by Seahorse assay, which measures Basal Oxygen Consumption Rate of live cells to provide insight into mitochondrial activity. | Assessed at baseline, week 4, and week 8. Change in baseline to week 4 is reported. | 
| Change in Mitochondrial Bioenergetics Measured by Basal Oxygen Consumption Rate at 8 Weeks (Basal Consumption) | Blood draw will be tested for mitochondrial function by Seahorse assay, which measures Basal Oxygen Consumption Rate of live cells to provide insight into mitochondrial activity. | Assessed at baseline, week 4, and week 8. Change in baseline to week 8 is reported. | 
| Change in Blood Cytokines Measured by TNF α Levels at 4 Weeks | Blood will be analyzed to detect changes in protein cytokine TNF α levels, an indicator for inflammation. | Assessed at baseline, week 4, and week 8. Change in baseline to week 4 is reported. | 
| Change in Blood Cytokines Measured by TNF α Levels at 8 Weeks | Blood will be analyzed to detect changes in protein cytokine TNF α levels, an indicator for inflammation | Assessed at baseline, week 4, and week 8. Change in baseline to week 8. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Functional Disability Inventory (Child and Adolescent) | The Functional Disability Inventory (FDI) Child and Adolescent questionnaire will be used to assess change in symptoms. Participants will rank physical trouble or difficulty completing 15 different daily activities (Eating regular meals, Being at school all day, Walking up stairs, etc.) on a scale of 0-4 for each item (0-No trouble, 1- A Little Trouble, 2- Some Trouble, 3- A Lot of Trouble, 4- Impossible). Higher total scores indicate more difficulty functioning due to physical health, based on a sum score of each item. Sum score interpretation cutoffs include: No/Minimal Disability (0-12), Mild Disability (13-20), Moderate Disability (21-29) and Severe Disability (≥30). | Assessed at baseline, week 4, and week 8. Score changes from baseline to week 4 and baseline to week 8 are reported. | 
| Change From Baseline in Symptom Intensity Questionnaire | Symptom Intensity Questionnaire score will be used to identify the most prominent 5 complaints, with intensity rated on a 10-point centimeter Likert scale. Participants write up to 5 of their most severe symptoms, and then rate those symptoms' severity from none (0) to worst you can possibly imagine (10) by placing a vertical line on the scale. Higher symptom ratings reflect higher symptom intensity & frequency. A 1-3 frequency level is a minimum level and indicates symptoms are occasional. A 4-6 frequency is a moderate level, meaning that symptoms are intermittent, coming and going. A 7-8 frequency is an indication that the symptoms are present more often than not but still not constant. A 9-10 frequency level is severe and indicates that symptoms are constant. The electronic data capture system's field validation used during the study automatically translated the participant-facing 0-10 slider scale placement into a score of 0-100, hence the reported mean values of over 10. | Assessed at baseline, week 4, and week 8. Changes per symptom score in baseline to week 4 and baseline to week 8 are reported. | 
| Change From Baseline in Pain Catastrophizing Scale (Child) | The Pain Catastrophizing Scale Child form (PCS-C) will be completed by the participant. The PCS-C is a modification of the adult Pain Catastrophizing Scale for use in children, measuring pain-related cognitions and the dimensions of helplessness, rumination and magnification. Participants rate how strong their feelings are about pain on a 5 point scale (0- Not at all, 1- To a slight degree, 2- To a moderate degree, 3- To a great degree, 4- All the time). Sum scores range from 0-52. Higher scores indicate higher levels of pain catastrophizing. A total PCS score of 30 represents a clinically relevant level of catastrophizing. | Assessed at baseline, week 4, and week 8. Score change in baseline to week 8 is reported. | 
| Change From Baseline in Revised Child Anxiety and Depression Scale | The Revised Child Anxiety and Depression Scale (RCADS) assesses children grades 3 to 12 containing subscales assessing for symptoms of anxiety and depression. Participants rate frequency of occurrences described in the items on a 4 point scale (0- Never, 1- Sometimes, 2- Often, or 3- Always). Sum scores of anxiety/depression items were assessed. Depression items: score range 0-30 Anxiety items: score range 0-18 Higher scores on both the depression & anxiety items indicate higher levels of depression & anxiety. Raw sum scores of both the depression & anxiety subscale items are translated to a T-score. T-scores below 65 represent low severity. T-scores between 65-70 represent medium severity and are on the borderline clinical threshold. T-scores above 70 represent high severity and are above the clinical threshold. A T-score of 50 indicates the population mean with a standard deviation of 10. | Assessed at baseline, week 4, and week 8. Changes in generalized anxiety & depression t-scores (translated from raw subscale scores) in baseline to week 4 and baseline to week 8 are reported. | 
| Change From Baseline in Functional Disability Inventory (Parent) | The Functional Disability Inventory (FDI) Parent questionnaire will be used to assess change in the participants symptoms as rated by the participants parent/guardian. Parents will rank their child's physical trouble or difficulty completing 15 different daily activities (Eating regular meals, Being at school all day, Walking up stairs, etc.) on a scale of 0-4 for each item (0-No trouble, 1- A Little Trouble, 2- Some Trouble, 3- A Lot of Trouble, 4- Impossible). Higher total scores indicate more difficulty functioning due to physical health, based on a sum score of each item. Sum score interpretation cutoffs include: No/Minimal Disability (0-12), Mild Disability (13-20), Moderate Disability (21-29) and Severe Disability (≥30). | Assessed at baseline, week 4, and week 8. Score changes from baseline to week 4 and baseline to week 8 are reported. | 
| Change From Baseline in Pain Catastrophizing Scale (Parent) | The Pain Catastrophizing Scale Parent form (PCS-P) will be completed by the parent or guardian of the participant. The PCS-P is a proxy questionnaire to the PCS-C, measuring the feelings the parent has when their child is in pain. Parents rate how strongly they feel when their child is in pain on a 5 point scale (0- Not at all, 1- To a slight degree, 2- To a moderate degree, 3- To a great degree, 4- All the time). Sum scores range from 0-52. Higher scores indicate higher levels of pain catastrophizing. A total PCS score of 30 represents a clinically relevant level of catastrophizing. | Assessed at baseline, week 4, and week 8. Score change from baseline to week 8 is reported. |