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This study evaluates the efficacy of auricular neurostimulation via an non-invasive percutaneous electrical nerve field stimulator in children and adults with 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Acute therapy: active vs sham percutaneous neurostimulation | Sham Comparator | Subject randomized to 5 days of active or sham neurostimulation therapy during the first illness cycle. With the second illness cycle, each subject will then cross over to the other therapy (active or sham). |
|
| Chronic therapy: active (open-label) percutaneous neurostimulation | Experimental | Each subject receives 6 consecutive weeks of active (open-label) neurostimulation therapy. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Percutaneous neurostimulation | Device | Auricular percutaneous neurostimulation |
|
| Measure | Description | Time Frame |
|---|---|---|
| Rhodes Index of Nausea, Vomiting & Retching (INVR) | 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. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Numeric Pain Scale | 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). | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Katja Kovacic, MD | Medical College of Wisconsin | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital of Wisconsin | Milwaukee | Wisconsin | 53226 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28826627 | Background | 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. | |
| 28526575 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Acute Therapy: Cross-over Active Neurostimulation | Subject randomized to 5 days of active vs sham neurostimulation therapy during the first illness cycle. With second illness cycle, each subject will cross over to the other arm for 5 days of active vs. sham neurostimulation therapy. Percutaneous neurostimulation: Auricular percutaneous neurostimulation |
| FG001 | Acute Therapy: Cross-over Sham Neurostimulation | Subject randomized to 5 days of active vs sham neurostimulation therapy during the first illness cycle. With second illness cycle, each subject will cross over to the other arm for 5 days of active vs. sham neurostimulation therapy. Percutaneous neurostimulation: Auricular percutaneous neurostimulation |
| FG002 | Chronic Therapy: Active (Open-label) Neurostimulation | Each participant receives active, open label percutaneous neurostimulation therapy x 6 consecutive weeks |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Acute therapy; 15 subjects enrolled; 4 dropped out and 1 ineligible for total of n=10 completed trial Chronic therapy: 32 subjects enrolled; 1 dropped out and 1 ineligible for total of n=30 completed trial
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| ID | Title | Description |
|---|---|---|
| BG000 | Acute Therapy: Active Neurostimulation | Each subject randomized to receive 5 days of active (vs. sham) neurostimulation therapy during the first illness cycle. With the next illness cycle, each subject will cross over to sham (or active) intervention for 5 days. Percutaneous neurostimulation: Auricular percutaneous neurostimulation |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Rhodes Index of Nausea, Vomiting & Retching (INVR) | 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. | Study design for Acute treatment arm was subsequently deemed unfeasible and the trial terminated early for the Acute treatment arm. | Posted | Mean | Standard Deviation | score on a scale | 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. |
|
6 months
Adverse events assessed at each encounter
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Acute Active Percutaneous Neurostimulation | Each subject randomized to active vs sham therapy during 1st illness cycle (5 days) after enrollment, then cross over to the other (active vs sham) during the 2nd illness cycle (5 days). Percutaneous neurostimulation: Auricular percutaneous neurostimulation |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Skin irritation | Skin and subcutaneous tissue disorders | Systematic Assessment | Mild skin irritation (reaction) to adhesive |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Katherine Siegel, Research Manager, Division of Pediatric Gastroenterology | Medical College of Wisconsin | 4142663915 | ksiegel@mcw.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 7, 2020 | Feb 22, 2023 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| C536228 | Familial cyclic vomiting syndrome |
| D008881 | Migraine Disorders |
| ID | Term |
|---|---|
| D051270 | Headache Disorders, Primary |
| D020773 | Headache Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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Arm 1 (Acute treatment): Each subject randomized to active vs sham therapy during 1st illness cycle after enrollment, then cross over to the other (active vs sham) during the 2nd illness cycle.
Arm 2 (Chronic treatment): Active, chronic (prophylactic) therapy (open label) x 6 consecutive weeks of intervention.
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Double blind, cross over study for Arm 1 (Acute treatment) only Arm 2: open-label
|
| Anxiety |
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). |
| 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). |
| Patient Reported Outcomes Measurement Information Systems- Health-Related Quality of Life | 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. | 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. |
| Functional Disability Inventory- Disability in Children | 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. | 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. |
| Disability in Adults | 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. | 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. |
| Symptom Response Scale | Global symptom improvement scale, score ranging from -7 to +7 (0=no change, positive score indicates improvement while negative score indicates worsening). | 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. |
| 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. |
| 28301217 | Background | 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. |
| 27843360 | Background | 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. |
| 37389229 | Derived | 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. |
| BG001 |
| Acute Therapy: Sham Neurostimulation |
Each subject randomized to receive 5 days of sham (vs active) neurostimulation therapy during the first illness cycle. With the next illness cycle, each subject will cross over to active (or sham) intervention for 5 days. Percutaneous neurostimulation: Auricular percutaneous neurostimulation |
| BG002 | Chronic Therapy; Active (Open-label) Neurostimulation | Active, open label neurostimulation therapy x 6 consecutive weeks. Percutaneous neurostimulation: Auricular percutaneous neurostimulation |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Frequency of emesis episodes | Number of Participants with More Than 1 Vomiting Cycle per Month | Count of Participants | Participants |
|
| Description |
|---|
| OG000 | Acute Therapy Arm: Active Neurostimulation | Subject randomized to active (vs sham) neurostimulation therapy during the first illness cycle for 5 days of therapy. With next illness cycle, each subject will cross over to the other (sham vs. active) intervention for 5 days. Percutaneous neurostimulation: Auricular percutaneous neurostimulation |
| OG001 | Acute Therapy Arm: Sham Neurostimulation | Subject randomized to sham (vs active) neurostimulation therapy during the first illness cycle for 5 days of therapy. With next illness cycle, each subject will cross over to the other (active vs sham) intervention for 5 days. Percutaneous neurostimulation: Auricular percutaneous neurostimulation |
| OG002 | Chronic Therapy Arm | Active, open label percutaneous neurostimulation therapy x 6 consecutive weeks |
|
|
| Secondary | Numeric Pain Scale | 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). | This outcome (daily pain severity) was designed for the Acute Therapy Arm only as it assesses daily pain during an acute intervention. The chronic therapy arm did not include this outcome measure due to the longer term treatment and therefore, there is no data for the chronic therapy arm. | Posted | Mean | Standard Deviation | score on a 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. |
|
|
|
| Secondary | Anxiety | 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). | Complete data captured on 26 participants in Chronic Therapy arm. No data captured on Acute Therapy Arm for this outcome measure as this arm deemed unfeasible due to subjects being too ill to return for on site visits and subsequently dropped out of study. Contrary to the daily surveys completed in home setting (outcome measure 2), data was not obtained for the on site visits at the end of therapy. | Posted | Median | Inter-Quartile Range | score on STAI state anxiety scale | 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). |
|
|
|
| Secondary | Patient Reported Outcomes Measurement Information Systems- Health-Related Quality of Life | 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. | Complete data capture on 27 participants (Chronic Therapy Arm). No data captured on Acute Therapy Arm for this outcome measure as this arm deemed unfeasible due to subjects being too ill to return for on site visits and subsequently dropped out of study. Contrary to the daily surveys completed in home setting (outcome measure 2), data was not obtained for the on site visits at the end of therapy. | Posted | Median | Inter-Quartile Range | score on a scale | 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. |
|
|
|
| Secondary | Functional Disability Inventory- Disability in Children | 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. | Complete data captured on 30 participants in Chronic Therapy arm. No data captured on Acute Therapy Arm for this outcome measure as this arm deemed unfeasible due to subjects being too ill to return for on site visits and subsequently dropped out of study. Contrary to the daily surveys completed in home setting (outcome measure 2), data was not obtained for the on site visits at the end of therapy. | Posted | Median | Inter-Quartile Range | score on a scale | 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. |
|
|
|
| Secondary | Disability in Adults | 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. | No data collected as no adult participants enrolled. | Posted | No | 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. |
|
|
| Secondary | Symptom Response Scale | Global symptom improvement scale, score ranging from -7 to +7 (0=no change, positive score indicates improvement while negative score indicates worsening). | Data captured on 29 participants in Chronic Therapy arm. | Posted | Median | Inter-Quartile Range | positive score on 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. |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 0 |
| 10 |
| EG001 | Acute Sham Percutaneous Neurostimulation | Each subject randomized to active vs sham therapy during 1st illness cycle (5 days) after enrollment, then cross over to the other (active vs sham) during the 2nd illness cycle (5 days). Percutaneous neurostimulation: Auricular percutaneous neurostimulation | 0 | 10 | 0 | 10 | 0 | 10 |
| EG002 | Chronic Percutaneous Neurostimulation | Chronic (prophylactic), active therapy (open label) x 6 consecutive weeks of intervention. Percutaneous neurostimulation: Auricular percutaneous neurostimulation | 0 | 30 | 0 | 30 | 7 | 30 |
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| Discomfort | General disorders | Systematic Assessment | Mild ear discomfort (throbbing) at site of electrode |
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| Bleeding | Blood and lymphatic system disorders | Systematic Assessment | Mild bleeding at site of electrode |
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| D009422 | Nervous System Diseases |
| End of therapy |
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| Follow-up |
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| Physical Function: End of therapy |
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| Physical Function: Follow-up |
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| Anxiety: Baseline |
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| Anxiety; End of therapy |
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| Anxiety: Follow-up |
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| Fatigue: Baseline |
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| Fatigue: End of therapy |
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| Fatigue: Follow-up |
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| Pain Interference: Baseline |
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| Pain Interference: End of therapy |
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| Pain Interference: Follow-up |
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| Functional disability: end of therapy |
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| Functional Disability: Follow-up |
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