Auricular Neurostimulation for Cyclic Vomiting Syndrome

Cyclic vomiting syndrome (CVS) is an difficult to treat and debilitating functional gastrointestinal disorder presenting with episodes of severe nausea and vomiting. Majority of children and adults with CVS have concurrent severe abdominal pain and migraine-features, rendering them incapacitated during the vomiting cycle.

The vagus nerve carries signals of nausea, vomiting and pain between the brain and the gastrointestinal tract and is part of the autonomic nervous system. The autonomic nervous system appears to be in imbalance in patients with CVS during a vomiting cycle. By stimulating a branch of the vagus nerve in the outer ear, this study aims to improve symptoms and quality of life in both children and adults with CVS.

Subjects in Acute treatment arm will be randomized to receive active vs sham (non-active) neurostimulation therapy for 5 days at the onset of a CVS cycle (1st illness period). They will then cross over to the other group (active vs sham) at the onset of the next CVS cycle (2nd illness period). Subjects in a separate Chronic (Prophylactic) treatment arm receive 6 consecutive weeks of active neurostimulation therapy (5 days/week). Pain, nausea, vomiting, anxiety, quality of life, potential side effects and overall symptom improvement will be monitored before and after therapy.

• Percutaneous neurostimulation (Device), also known as Neuro-Stim System (NSS)-2 BRIDGE: Auricular percutaneous neurostimulation

Primary outcomes

• Rhodes Index of Nausea, Vomiting & Retching (INVR) [Acute arm: at the start of the first and second illness cycle through next 7 days for each illness cycle (active and sham therapy). Chronic arm: from date of baseline assessment (therapy start date) through 6 weeks of therapy.]: Acute therapy arm: Daily nausea and vomiting severity assessed by validated scale 0-32 (0=no symptoms; 32=worse possible nausea/vomiting) with higher scores indicating worse outcomes (greater nausea/vomiting). Daily scores for baseline (day 1) and end of therapy (day 7) were compared for both active and sham groups. Chronic therapy arm: Daily nausea and vomiting severity assessed by validated scale 0-32 (0=no symptoms; 32=worse possible nausea/vomiting) with higher scores indicating worse outcomes (greater nausea/vomiting). Daily scores were averaged for each week of the 6 weeks of therapy and compared between a baseline assessment and week 6 of therapy.

Secondary outcomes

• Numeric Pain Scale [From date of baseline assessment (therapy start date) through next 7 days for each cycle of therapy with day 7 reported as end of therapy.]: Daily pain severity assessed by numeric pain scale 0-10 (0=no pain; 10=worst possible pain) with higher scores indicating worse outcome (greater pain).
• Anxiety [From date of baseline assessment (therapy start date) to end of therapy. For Chronic therapy arm, end of therapy= 6 weeks. For Acute therapy arm, end of therapy = day 7 (on site).]: State-Trait Anxiety Inventory for Children and Adults. State and trait anxiety is assessed by a validated instrument (raw score 20=minimum anxiety; 60=maximum anxiety) with higher scores indicating worse outcomes (greater anxiety). Scores are covered to standardized T scores (mean 50; standard deviation 10).
• Patient Reported Outcomes Measurement Information Systems- Health-Related Quality of Life [From date of baseline assessment (therapy start date) to end of therapy and at 3 months follow-up. For Chronic therapy arm, end of therapy = 6 weeks. For Acute therapy arm, end of therapy = day 7.]: Patient Reported Outcomes Measurement Information Systems (PROMIS). Quality-of-life outcome measure that assesses physical, emotional and psychosocial functioning across six domains (Physical function, Anxiety, Fatigue, Pain Interference). Raw score 37= maximum/best quality of life; raw score 185= minimum/worst quality of life. Scores are covered to standardized T scores (mean 50; SD 10). A lower score indicates improved quality of life.
• Functional Disability Inventory- Disability in Children [From date of baseline assessment (therapy start date) to end of therapy and 3 months follow-up. For Chronic therapy arm, end of therapy = 6 weeks. For Acute therapy arm, end of therapy = 7 days.]: Functional Disability Inventory. A 15-item self-report measure of the degree that children experience difficulty in physical and psychosocial functioning due to impaired physical health. Higher scores indicates worse outcomes (0=minimal disability; 60=maximum disability) and worse disability.
• Disability in Adults [Anticipated assessment from date of baseline assessment (therapy start date) and end of therapy for each cycle of therapy as well as follow-up visit after end of therapy. However, no adult participants were enrolled.]: Sheehan Disability Scale assessing disability and impairment on a scale 0-10 with higher scores indicating more disability. Three sub scales: 1) school/work, 2) social life and 3) family life are assessed (scale 0-10) with a total score reflecting the sum of the 3 subscales (total score range 0-30 with higher score indicating more disability). No data collected as no adult participants enrolled.
• Symptom Response Scale [From date of baseline assessment (therapy start date) to global symptom assessment at end of therapy. For Chronic therapy arm, end of therapy = 6 weeks. For Acute therapy arm, end of therapy = 7 days.]: Global symptom improvement scale, score ranging from -7 to +7 (0=no change, positive score indicates improvement while negative score indicates worsening).

Sex: All, ages: 8 Years to 65 Years

Inclusion Criteria:

* Meeting Rome IV Pediatric or Adult criteria for Cyclic Vomiting Syndrome (CVS)
* Concurrent abdominal pain with CVS cycle
* English-speaking
* Lack of other explanation for symptoms
* Either predictable, 'calendar-timed' episodes or prodromal symptoms for 12-24 hours that are predictive of episodes onset

Exclusion Criteria:

* Medically complex and/or suffering from medical condition that may explain symptoms
* Taking a medication that may explain symptoms
* Significant developmental delays
* Patients treated with a new drug affecting the central nervous system within one week of enrollment
* Infection or severe dermatological condition of ear
* Stable vital signs
* No currently implanted electrical device
* For adults (and adolescents as applicable): pregnancy, severe cardiopulmonary disease, concurrent chronic marijuana use (>2 times/month over past 6 months prior to enrollment)

Participant flow

Outcome results

• Rhodes Index of Nausea, Vomiting & Retching (INVR) (Primary), Mean, score on a scale: Acute Therapy Arm: Active Neurostimulation 3.25 +/- 3.95; Acute Therapy Arm: Sham Neurostimulation 5.80 +/- 9.17; Chronic Therapy Arm 10.43 +/- 9.78
• Numeric Pain Scale (Secondary), Mean, score on a scale: Acute Therapy: Active 4 +/- 0; Acute Therapy: Sham 4.7 +/- 3.4; Chronic Therapy Arm
• Anxiety (Secondary), Median, score on STAI state anxiety scale: Chronic Therapy: Arm 2 63.5 (52 to 70); Acute Therapy; Active 28 (25 to 36); Acute Therapy: Sham 29 (26 to 34.5)
• Patient Reported Outcomes Measurement Information Systems- Health-Related Quality of Life (Secondary), Median, score on a scale: Chronic Therapy: Arm 2 25.4 (22.8 to 28.9); Acute Therapy: Active 13.0 (8.0 to 23.0); Acute Therapy; Sham 10.0 (6.0 to 13.0)
• Functional Disability Inventory- Disability in Children (Secondary), Median, score on a scale: Chronic Therapy: Arm 1 47.5 (41 to 53); Acute Therapy: Active 45.5 (25.5 to 49); Acute Therapy: Sham 44 (39 to 47)
• Disability in Adults (Secondary)
• Symptom Response Scale (Secondary), Median, positive score on Symptom Response Scale: Chronic Therapy: Arm 1 5 (3 to 6); Acute Therapy: Active 5 (4 to 7); Acute Therapy; Sham 0 (0 to 0)

Adverse events

Time frame: 6 months

Other adverse events by term

• Kovacic K, Hainsworth K, Sood M, Chelimsky G, Unteutsch R, Nugent M, Simpson P, Miranda A. Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Lancet Gastroenterol Hepatol. 2017 Oct;2(10):727-737. doi: 10.1016/S2468-1253(17)30253-4. Epub 2017 Aug 18. PMID 28826627
• Babygirija R, Sood M, Kannampalli P, Sengupta JN, Miranda A. Percutaneous electrical nerve field stimulation modulates central pain pathways and attenuates post-inflammatory visceral and somatic hyperalgesia in rats. Neuroscience. 2017 Jul 25;356:11-21. doi: 10.1016/j.neuroscience.2017.05.012. Epub 2017 May 17. PMID 28526575
• Miranda A, Taca A. Neuromodulation with percutaneous electrical nerve field stimulation is associated with reduction in signs and symptoms of opioid withdrawal: a multisite, retrospective assessment. Am J Drug Alcohol Abuse. 2018;44(1):56-63. doi: 10.1080/00952990.2017.1295459. Epub 2017 Mar 16. PMID 28301217
• Roberts A, Sithole A, Sedghi M, Walker CA, Quinn TM. Minimal adverse effects profile following implantation of periauricular percutaneous electrical nerve field stimulators: a retrospective cohort study. Med Devices (Auckl). 2016 Nov 3;9:389-393. doi: 10.2147/MDER.S107426. eCollection 2016. PMID 27843360
• Results publication: Karrento K, Zhang L, Conley W, Qazi Z, Venkatesan T, Simpson P, Li BUK. Percutaneous electrical nerve field stimulation improves comorbidities in children with cyclic vomiting syndrome. Front Pain Res (Lausanne). 2023 Jun 14;4:1203541. doi: 10.3389/fpain.2023.1203541. eCollection 2023. PMID 37389229

• Study Protocol and Statistical Analysis Plan (PDF, 2020-02-07)

• Katja Kovacic, MD, Principal investigator, Medical College of Wisconsin