Functional Disorder of Intestine, Nausea Persistent
Conditions
Brief summary
This study evaluates the effectiveness of a neurostimulator applied to the outer ear for adolescents with functional gastrointestinal disorders. The neurostimulator provides nerve stimulation to a branch of the vagus nerve which is thought to be involved in transmission of pain signals. Half of the study subjects will receive an active nerve stimulator while the other half will receive an inactive one.
Detailed description
The vagus nerve innervates the gastrointestinal tract and influences the autonomic nervous system. It is thought to carry signals of discomfort and nausea to the brain where it is interpreted. The autonomic nervous system may be in imbalance in patients with functional gastrointestinal disorders. By stimulating a branch of the vagus nerve in the outer ear, this study aims to improve symptoms and quality of life in adolescents with functional abdominal pain with or without nausea. Subjects will be randomized into two groups: 1) neurostimulation versus 2) sham. They will receive either an active or non-active (sham group) device for 5 days each week x 4 weeks total. Pain, nausea, anxiety, quality of life, potential side effects and overall symptom improvement will be monitored weekly for the entire study as well as after the study is completed.
Interventions
DEVICENeurostimulator
Non-invasive, battery operated neurostimulator of the external ear worn for 5 days each week x 4 weeks.
DEVICESham
Inactive neurostimulator device pre-programmed to be inactive. To be worn for 5 days each week x 4 weeks.
Sponsors
American Neurogastroenterology and Motility Society
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
11 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Adolescents with a major complaint of abdominal pain (minimum 3/10 in severity) with or without nausea (minimum 3/10 in severity) of unclear etiology, who are English-speaking and willing to participate and consent to the study and who have a parent willing to participate. * Patients with symptoms of minimum three times per week for a duration of two months or greater * Intact external ear that is free of infection or severe dermatological conditions. * Stable vital signs for their respective age
Exclusion criteria
* Medically complex children or those who take a medication or suffer from an organic disease that can explain symptoms will be excluded from participation. * Children or parents, who have developmental delay, will be excluded due to difficulties in accurately completing the questionnaires and assessing symptoms. * History of seizures * Currently implanted electrical device * Orthostatic hypotension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Frequency-Severity-Duration Scale (PFSD) Score | Change from Baseline to Week 4 | One-page, 6-item pain measure assessing pain symptoms over the past week. Measures the typical and worst pain intensity, frequency and duration over the past week in units on a scale from 0 to 10 (10 being the worst pain imaginable). Worst pain = primary outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nausea Profile | Change from Baseline to week 4 in Nausea Profile score. | Two page, 17-item questionnaire which measures the subjective experience of nausea on a scale from 0 (not at all) to 9 (severely) across three dimensions: 1) somatic distress; 2) gastrointestinal distress and 3) emotional distress. Total score 153. |
| State-Trait Anxiety Inventory for Children (STAI-C) | Change from Baseline (Pre) to 2-3 months after end of therapy (Post) | State-Trait Anxiety Inventory for Children (STAI-C). State anxiety measured by 20-item questionnaire assessing anxiety at a particular moment in time on a 3-point rating scale. Raw scores (range 20-60) were converted to normalized T-Scores based on a population of healthy school children (mean=50; standard deviation=10) with higher score indicating worse outcome. Effects of intervention on state anxiety was assessed before (pre) and after (post) therapy. |
| Patient Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health (PGH-7) | Change from Baseline (Pre) to 2-3 months after end of therapy (Post) | A 7-item instrument that measures quality of life in relation to health. Each question has five response options (scored 1-5 units on a scale). A total raw sum score is generated, ranging from lowest score of 7 and highest score of 35 with higher scores indicating better outcome (improved quality of life). The raw score is converted to a standardized T-score (mean=50; standard deviation=10) based on a population of healthy children. T-scores were compared before (Pre) and after (Post) treatment intervention. |
| Functional Disability Inventory (FDI) | Change from Baseline (Pre) to 2-3 months after end of therapy (Post) | 15-item instrument, each question rated on a five-point scale (0=no trouble to 4=impossible), indicating how much difficulty subjects have doing common childhood activities because of their physical health. A total score is summed (range 0-60) with higher score indicating worse outcome (greater pain-related disability). Scored were compared before (Pre) and after (Post) treatment intervention. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III (QPGS-RIII), Reporting the Number of Participants With Specific Diagnoses | Baseline only (diagnostic criteria) | Nine-page, validated, parent-report questionnaire that assesses symptoms associated with pediatric functional GI disorders to diagnose the following specific Rome III criteria: Irritable Bowel Syndrome, Functional Dyspepsia, Abdominal Migraine, Functional Abdominal Pain and Functional Abdominal Pain Syndrome. The number of participants with these specific diagnoses at baseline were reported, including overlapping diagnoses. |
Countries
United States
Participant flow
Recruitment details
Eligible subjects ages 11-18 years, recruited from the outpatient Gastroenterology clinic at the Children's Hospital of Wisconsin between September 2015 and November 2016.
Pre-assignment details
Subjects were excluded if there were any changes to their current medications or any new medications added during the two weeks prior to study start. Any subject with a new diagnosis of an organic medical condition was also excluded.
Participants by arm
| Arm | Count |
|---|---|
| Neurostimulator Auricular neurostimulator treatment x 5 days each week for 4 consecutive weeks
Neurostimulator: Non-invasive, battery operated neurostimulator of the external ear worn for 5 days each week x 4 weeks. | 57 |
| Sham Neurostimulator Inactive auricular neurostimulator treatment x 5 days each week for 4 consecutive weeks
Sham: Inactive neurostimulator device pre-programmed to be inactive. To be worn for 5 days each week x 4 weeks. | 47 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Organic disorder diagnosed | 2 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 5 |
Baseline characteristics
| Characteristic | Neurostimulator | Sham Neurostimulator | Total |
|---|---|---|---|
| Age, Continuous | 15.3 years | 15.6 years | 15.3 years |
| Race/Ethnicity, Customized Ethnicity African American | 6 Participants | 2 Participants | 8 Participants |
| Race/Ethnicity, Customized Ethnicity Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnicity White | 49 Participants | 44 Participants | 93 Participants |
| Region of Enrollment United States | 57 Participants | 47 Participants | 104 Participants |
| Sex: Female, Male Female | 51 Participants | 43 Participants | 94 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 57 | 0 / 47 |
| other Total, other adverse events | 4 / 57 | 6 / 47 |
| serious Total, serious adverse events | 0 / 57 | 0 / 47 |
Outcome results
Primary
Pain Frequency-Severity-Duration Scale (PFSD) Score
One-page, 6-item pain measure assessing pain symptoms over the past week. Measures the typical and worst pain intensity, frequency and duration over the past week in units on a scale from 0 to 10 (10 being the worst pain imaginable). Worst pain = primary outcome.
Time frame: Change from Baseline to Week 4
Population: Modified intent to treat population (all subjects who received minimum one week of therapy and with at least two available data points). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neurostimulator | Pain Frequency-Severity-Duration Scale (PFSD) Score | 5.0 units on a scale |
| Sham Neurostimulator | Pain Frequency-Severity-Duration Scale (PFSD) Score | 7.0 units on a scale |
p-value: 0.00395% CI: [1.37, 2.93]Wilcoxon (Mann-Whitney)
Secondary
Functional Disability Inventory (FDI)
15-item instrument, each question rated on a five-point scale (0=no trouble to 4=impossible), indicating how much difficulty subjects have doing common childhood activities because of their physical health. A total score is summed (range 0-60) with higher score indicating worse outcome (greater pain-related disability). Scored were compared before (Pre) and after (Post) treatment intervention.
Time frame: Change from Baseline (Pre) to 2-3 months after end of therapy (Post)
Population: Modified intent to treat population (all subjects who received minimum one week of therapy and with at least two available data points). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurostimulator | Functional Disability Inventory (FDI) | FDI Pre | 17.0 units on a scale |
| Neurostimulator | Functional Disability Inventory (FDI) | FDI Post | 11 units on a scale |
| Sham Neurostimulator | Functional Disability Inventory (FDI) | FDI Pre | 17.0 units on a scale |
| Sham Neurostimulator | Functional Disability Inventory (FDI) | FDI Post | 17.0 units on a scale |
Secondary
Nausea Profile
Two page, 17-item questionnaire which measures the subjective experience of nausea on a scale from 0 (not at all) to 9 (severely) across three dimensions: 1) somatic distress; 2) gastrointestinal distress and 3) emotional distress. Total score 153.
Time frame: Change from Baseline to week 4 in Nausea Profile score.
Population: Modified intent to treat population (all subjects who received minimum one week of therapy and with at least two available data points). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neurostimulator | Nausea Profile | 25.5 units on a scale |
| Sham Neurostimulator | Nausea Profile | 20.0 units on a scale |
Secondary
Patient Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health (PGH-7)
A 7-item instrument that measures quality of life in relation to health. Each question has five response options (scored 1-5 units on a scale). A total raw sum score is generated, ranging from lowest score of 7 and highest score of 35 with higher scores indicating better outcome (improved quality of life). The raw score is converted to a standardized T-score (mean=50; standard deviation=10) based on a population of healthy children. T-scores were compared before (Pre) and after (Post) treatment intervention.
Time frame: Change from Baseline (Pre) to 2-3 months after end of therapy (Post)
Population: Modified intent to treat population (all subjects who received minimum one week of therapy and with at least two available data points). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurostimulator | Patient Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health (PGH-7) | PROMIS Pre | 42.1 T-score |
| Neurostimulator | Patient Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health (PGH-7) | PROMIS Post | 42.1 T-score |
| Sham Neurostimulator | Patient Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health (PGH-7) | PROMIS Pre | 37.2 T-score |
| Sham Neurostimulator | Patient Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health (PGH-7) | PROMIS Post | 38.8 T-score |
Secondary
State-Trait Anxiety Inventory for Children (STAI-C)
State-Trait Anxiety Inventory for Children (STAI-C). State anxiety measured by 20-item questionnaire assessing anxiety at a particular moment in time on a 3-point rating scale. Raw scores (range 20-60) were converted to normalized T-Scores based on a population of healthy school children (mean=50; standard deviation=10) with higher score indicating worse outcome. Effects of intervention on state anxiety was assessed before (pre) and after (post) therapy.
Time frame: Change from Baseline (Pre) to 2-3 months after end of therapy (Post)
Population: Modified intent to treat population (all subjects who received minimum one week of therapy and with at least two available data points). Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurostimulator | State-Trait Anxiety Inventory for Children (STAI-C) | State Anxiety Pre | 54.0 T-score |
| Neurostimulator | State-Trait Anxiety Inventory for Children (STAI-C) | State Anxiety Post | 52.0 T-score |
| Sham Neurostimulator | State-Trait Anxiety Inventory for Children (STAI-C) | State Anxiety Pre | 54.0 T-score |
| Sham Neurostimulator | State-Trait Anxiety Inventory for Children (STAI-C) | State Anxiety Post | 54.0 T-score |
Other Pre-specified
Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III (QPGS-RIII), Reporting the Number of Participants With Specific Diagnoses
Nine-page, validated, parent-report questionnaire that assesses symptoms associated with pediatric functional GI disorders to diagnose the following specific Rome III criteria: Irritable Bowel Syndrome, Functional Dyspepsia, Abdominal Migraine, Functional Abdominal Pain and Functional Abdominal Pain Syndrome. The number of participants with these specific diagnoses at baseline were reported, including overlapping diagnoses.
Time frame: Baseline only (diagnostic criteria)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neurostimulator | Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III (QPGS-RIII), Reporting the Number of Participants With Specific Diagnoses | Irritable Bowel Syndrome | 28 Participants |
| Neurostimulator | Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III (QPGS-RIII), Reporting the Number of Participants With Specific Diagnoses | Functional Dyspepsia | 12 Participants |
| Neurostimulator | Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III (QPGS-RIII), Reporting the Number of Participants With Specific Diagnoses | Abdominal Migraine | 16 Participants |
| Neurostimulator | Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III (QPGS-RIII), Reporting the Number of Participants With Specific Diagnoses | Functional Abdominal Pain | 1 Participants |
| Sham Neurostimulator | Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III (QPGS-RIII), Reporting the Number of Participants With Specific Diagnoses | Functional Abdominal Pain | 0 Participants |
| Sham Neurostimulator | Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III (QPGS-RIII), Reporting the Number of Participants With Specific Diagnoses | Irritable Bowel Syndrome | 23 Participants |
| Sham Neurostimulator | Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III (QPGS-RIII), Reporting the Number of Participants With Specific Diagnoses | Abdominal Migraine | 13 Participants |
| Sham Neurostimulator | Questionnaire on Pediatric Gastrointestinal Symptoms, Rome III (QPGS-RIII), Reporting the Number of Participants With Specific Diagnoses | Functional Dyspepsia | 11 Participants |