Migraine, Pain
Conditions
Brief summary
The researchers propose studying Gulf veterans with Gulf War Illness (GWI), characterized by a problem with widespread pain. Besides their pain, the researchers will also assess the effect of vagus nerve stimulation (VNS) in alleviating migraine headache, another complaint of Gulf veterans, which is common in the presence of widespread pain. Importantly, the researchers are partnering with a company that has made a hand-held device that allows for stimulation of the vagus nerve without the need for surgery; it works by the patient putting it on the skin overlying the vagus nerve in their neck and then turning it on for 120 second periods three times a day. The device is programmed to deliver only 6 bouts of stimulation per day - one to each side of the neck three times a day; it is then inactive until the next day. The fact that this device can be used without surgery and is non-invasive makes it extremely practical for use. After collecting pre-treatment measurement of pain severity and headache severity, veterans will receive either the actual active VNS device or an inactive device, which does not stimulate the nerve. Veterans will use their device for ten weeks - providing similar information periodically over this period by responding to questions about the severity of their pain and headaches, They will then return to the Center for the final phase of the study where all veterans will receive active devices. Ten weeks later, they will return to the Center to provide information to allow the investigators to gain further knowledge as to the effectiveness of actual VNS in relieving pain - both throughout the body and in the head.
Detailed description
The Three Phases of the Study Subject Identification Phase of Study face to face visit at the War Related Illness & Injury Study Center at the East Orange Veterans Administration Medical Center (EOVAMC). Blinded Phase of Study Office Visit \[first time at Icahn School of Medicine at Mount Sinai. (ISMMS)\] Subjects randomized to either VNS device or inactive device. Open Label Phase of Study All subjects receive the VNS device
Interventions
DEVICEVNS device
Hand held device to use for self administration of vagus nerve stimulation.
DEVICEInactive device
Hand held device to use for self administration of simulated vagus nerve stimulation.
Sponsors
Benjamin Natelson
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
42 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
To be eligible for enrollment in the Study, patients must meet all of the following criteria: * Patient is a veteran of the 1990-91 Gulf War, aged at least 42 years old * Patient fulfills Kansas criteria for Gulf War Illness including endorsement of musculoskeletal pain at moderate or severe intensities. This means patient has endorsed symptoms in at least 3 of the following problem areas: Fatigue/sleep; musculoskeletal pain; cognitive and mood; Gastrointestinal; respiratory; skin. * Patient has widespread pain as evidenced by endorsement of pain in at least 3 bodily quadrants plus in the axial skeleton * Patient has a median 24 hour widespread pain score of at least 5 on a 0 to 10 visual analog scale (VAS) with data taken on five days * To be considered as having migraine, the patient must fulfill International Headache Society (IHS) criteria, and it should have been present for at least one year prior to entry into the study * Patient agrees to use the study device as intended, follow all of the requirements of the study including completion of diary after each self-treatment, follow-up visit requirements, complete self assessment questionnaires as scheduled, and report any adverse device effects to the study center within 24 hours of such adverse device effect. * Patient is able to provide written Informed Consent.
Exclusion criteria
Patients with any of the following will not be eligible for enrollment: * Patient has a history of intracranial aneurysm, intracranial hemorrhage, brain tumor or significant head trauma. * Patient has in the opinion of the investigator a clinically relevant structural abnormality at the gammaCore-R treatment site (e.g., neoplasm, lymphadenopathy, previous surgery, neoplasm or abnormal anatomy). * Patient has pain at the gammaCore treatment site (eg, dysesthesia, neuralgia, cervicalgia). * Patient has other significant pain problem (e.g., cancer pain or other head or facial pain disorder) that in the opinion of the investigator may confound the study assessments. * Patient has known or suspected severe cardiac disease (e.g., symptomatic coronary artery disease, prior myocardial infarction, congestive heart failure (CHF), significant premature ventricular contraction) or a history of cardiac arrhythmia. * Patient has known or suspected cerebrovascular disease (e.g., prior stroke or transient ischemic attack, symptomatic carotid artery disease, prior carotid endarterectomy or other vascular neck surgery). * Patient's electrocardiogram shows evidence of heart disease or arrhythmia including an abnormal baseline ECG (e.g. second and third degree heart block, prolonged QT interval (corrected QT (QTcB) interval \>470 msec for women and \> 450 for men), atrial fibrillation, atrial flutter, history of ventricular tachycardia or ventricular fibrillation, or clinically significant premature ventricular contraction) or a history of cardiac arrhythmia. * Patient has had a previous cervical vagotomy. * Patient has uncontrolled high blood pressure (systolic bp \>160, or diastolic bp \> 100) after 3 measurements within 24 hours. * Patient is currently implanted with an electrical and/or neurostimulator device (e.g. cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain stimulator, spinal stimulator, bone growth stimulator, or cochlear implant, Sphenopalatine ganglion stimulator or Occipital nerve stimulator). * Patient has been implanted with metal cervical spine hardware or has a metallic implant near the gammaCore-R stimulation site. * Patient has a history of significant syncope within the last 5 years. * Patient has a history of non-epileptic or epileptic seizures within the last 5 years. * Patient, in the opinion of the investigator, has a known history or suspicion of substance abuse or addiction within the last 5 years. * Patient, in the opinion of the investigator/research staff, the patient is incapable of operating the gammaCore-R device as intended and performing the data collection procedures. * Patient has a psychiatric or cognitive disorder and/or behavioral problem which in the opinion of the clinician may interfere with the study (e.g. Bipolar Disorder, depressive disorder with psychotic features, Specific Phobia, Acute Stress Disorder). * Patient is pregnant or thinking of becoming pregnant in the next 6 months, or is of childbearing years and unwilling to use an accepted form of birth control or is unwilling to undergo pregnancy testing. * Patient is nursing * Patient has undergone botulinum toxin (BOTOX) injections of the head and/or neck in the last 3 months. * Patient is participating or has participated in any other therapeutic clinical investigation during the last 30 days. * Patient belongs to a vulnerable population or has any condition such that his or her ability to provide informed consent, comply with follow-up requirements, or provide self-assessments is compromised (e.g., homeless, developmentally disabled, prisoner). * Patient has evidence of suicidality based on the Columbia Suicide Screening test * Patient has previously used a gammaCore device. * Patient is the spouse or housemate of someone else in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analog Scale (VAS) to Assess Change of Widespread Pain | 10 and 20 weeks | Patients used the Pain Visual Analog Scale (0-10; 0=No pain, 10=Worst pain possible) to rate their average level of pain over the last 24 hours. The median value for each individual's ratings over 5 consecutive days immediately prior to the end of the intervention period was recorded and then the average was calculated for each group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Global Improvement of Change (PGIC) | 10 and 20 weeks | PGIC is a 7-point scale used to quantify a patient's rating of overall improvement. Patients rate their change from 1 (no change or gotten worse) to 7 (considerable improvement). Higher scores indicate greater improvement since starting the intervention. |
| Physical Function Subscale From the Short Form Health Survey (SF-36) | 10 and 20 weeks | A normalized indicator of physical functioning with a range from 0-100. Higher scores indicate fewer limitations to activity. |
| Number of Headache Days Collected From the Migraine Disability Assessment (MIDAS). | 10 and 20 weeks | Participants are asked to indicate the number of days in the last 3 months during which they experienced a headache. If a headache lasted more than 1 day, they are instructed to count each day. Scores are expected between 0-90 with higher numbers corresponding to a greater number of headache days. |
| Depression Subscale From the Hospital Anxiety and Depression Scale (HADS) | 10 and 20 weeks | The HADS is a 14-item scale intended to quantify symptoms of depression and anxiety. Scores range from 0-21 on each subscale (Anxiety and Depression) with higher scores indicating a greater number of symptoms. |
Countries
United States
Participant flow
Recruitment details
We started with 29 veterans, recruited at the East Orange VA, who agreed to participate. Of these, 27 actually came to the Icahn School of Medicine at Mount Sinai where they signed an informed consent and were randomized. From that sample, 20 veterans completed the blinded phase of the study and 15 completed the entire study including open trial.
Participants by arm
| Arm | Count |
|---|---|
| VNS Device Vagus Nerve Stimulation (VNS) hand held device - subjects to utilize the VNS hand held device for 20 weeks total, putting it on the skin overlying the vagus nerve in their neck and then turning it on for 120 second periods three times a day. The device is programmed to deliver only 6 bouts of stimulation per day - one to each side of the neck three times a day
VNS device: Hand held device to use for self administration of vagus nerve stimulation. | 13 |
| Inactive Device Inactive hand held device - subjects to utilize the inactive device for 10 weeks and then will receive the VNS device for the next 10 weeks.
VNS device: Hand held device to use for self administration of vagus nerve stimulation.
Inactive device: Hand held device to use for self administration of simulated vagus nerve stimulation. | 14 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Blinded Phase | Lost to Follow-up | 2 | 2 |
| Blinded Phase | Withdrawal by Subject | 1 | 2 |
| Open Label Phase | Lost to Follow-up | 3 | 0 |
| Open Label Phase | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | VNS Device | Inactive Device | Total |
|---|---|---|---|
| Age, Continuous | 52.92 years STANDARD_DEVIATION 7.11 | 55.46 years STANDARD_DEVIATION 5.72 | 54.19 years STANDARD_DEVIATION 6.46 |
| Depression subscale from the Hospital Anxiety and Depression Scale (HADS) | 9.46 Units on a scale STANDARD_DEVIATION 2.26 | 11.00 Units on a scale STANDARD_DEVIATION 1.88 | 10.26 Units on a scale STANDARD_DEVIATION 2.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 12 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of Headache Days collected from the Migraine Disability assessment (MIDAS) | 8.38 Days STANDARD_DEVIATION 9.59 | 14.21 Days STANDARD_DEVIATION 24.28 | 11.41 Days STANDARD_DEVIATION 18.6 |
| Pain Visual Analog Scale (0-10) | 6.23 units on a scale STANDARD_DEVIATION 0.73 | 6.82 units on a scale STANDARD_DEVIATION 1.23 | 6.54 units on a scale STANDARD_DEVIATION 1.05 |
| Physical Function Subscale from the Short Form Health Survey (SF-36) | 46.15 Normalized units on a scale STANDARD_DEVIATION 22.28 | 40.00 Normalized units on a scale STANDARD_DEVIATION 22.01 | 42.96 Normalized units on a scale STANDARD_DEVIATION 21.94 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 7 Participants | 10 Participants | 17 Participants |
| Region of Enrollment United States | 13 participants | 14 participants | 27 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 12 Participants | 13 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 14 |
| other Total, other adverse events | 9 / 13 | 9 / 14 |
| serious Total, serious adverse events | 1 / 13 | 0 / 14 |
Outcome results
Primary
Visual Analog Scale (VAS) to Assess Change of Widespread Pain
Patients used the Pain Visual Analog Scale (0-10; 0=No pain, 10=Worst pain possible) to rate their average level of pain over the last 24 hours. The median value for each individual's ratings over 5 consecutive days immediately prior to the end of the intervention period was recorded and then the average was calculated for each group.
Time frame: 10 and 20 weeks
Population: The 10-week measure includes only those individuals who completed the blinded phase of the study. The 20-week measure includes only those individuals who completed the open label phase of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VNS Device | Visual Analog Scale (VAS) to Assess Change of Widespread Pain | 10 weeks | 4.70 Units on a scale | Standard Deviation 2.41 |
| VNS Device | Visual Analog Scale (VAS) to Assess Change of Widespread Pain | 20 weeks | 5.43 Units on a scale | Standard Deviation 2.07 |
| Inactive Device | Visual Analog Scale (VAS) to Assess Change of Widespread Pain | 10 weeks | 5.40 Units on a scale | Standard Deviation 2.27 |
| Inactive Device | Visual Analog Scale (VAS) to Assess Change of Widespread Pain | 20 weeks | 3.56 Units on a scale | Standard Deviation 1.4 |
Comparison: A power analysis was conducted with G\*Power, specifying a standard Type I error (α = .05) and desired power of .80. Results indicated that a total sample of 26 would be sufficient. Below are the results of the intent-to-treat analysis. Patients that did not complete the assessment after the blinded phase had their baseline scores carried forward. Post-intervention pain severity was regressed on pre-intervention pain severity and condition, using an ANCOVA model.p-value: 0.47ANCOVA
Comparison: Below are the results of the per protocol analysis. Patients that did not complete the assessment after the blinded phase are not included limiting the sample to 10 subjects in each condition (N=20). Post-intervention pain severity was regressed on pre-intervention pain severity and condition, using an ANCOVA model.p-value: 0.58ANCOVA
Primary
Visual Analog Scale (VAS) to Assess Change of Widespread Pain
Patients used the Pain Visual Analog Scale (0-10; 0=No pain, 10=Worst pain possible) to rate their average level of pain over the last 24 hours. The median value for each individual's ratings over 5 consecutive days immediately prior to the end of the intervention period was recorded and then the average was calculated for each group.
Time frame: Baseline and 20 weeks
Population: Regardless of the original condition assignment, outcomes from baseline and after the open-label period are compared. All patients received at least 10 weeks of active VNS therapy.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VNS Device | Visual Analog Scale (VAS) to Assess Change of Widespread Pain | Baseline | 6.18 Units on a scale | Standard Deviation 0.82 |
| VNS Device | Visual Analog Scale (VAS) to Assess Change of Widespread Pain | 20 weeks | 4.43 Units on a scale | Standard Deviation 1.94 |
Comparison: Regardless of original condition assignment, patients' 2.5-month pain scores at the end of the open label phase were compared to their baseline scores using a dependent samples t-test. Below are the results of the intent-to-treat analysis. Patients that did not complete the assessment after the open-label phase had their most recent score carried forward. All patients included in this comparison received at least 10 weeks of VNS therapy.p-value: 0.004t-test, 2 sided
Comparison: Regardless of original condition assignment, patients' 2.5-month pain scores at the end of the open label phase were compared to their baseline scores using a dependent samples t-test. Below are the results of the per protocol analysis. Patients that did not complete the assessment after the open-label phase were excluded. All patients included in this comparison received at least 10 weeks of VNS therapy.p-value: 0.005t-test, 2 sided
Secondary
Depression Subscale From the Hospital Anxiety and Depression Scale (HADS)
The HADS is a 14-item scale intended to quantify symptoms of depression and anxiety. Scores range from 0-21 on each subscale (Anxiety and Depression) with higher scores indicating a greater number of symptoms.
Time frame: 10 and 20 weeks
Population: The 10-week measure includes only those individuals who completed the blinded phase of the study. The 20-weel measure includes only those individuals who completed the open label phase of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VNS Device | Depression Subscale From the Hospital Anxiety and Depression Scale (HADS) | 10 weeks | 9.00 Units on a scale | Standard Deviation 2.26 |
| VNS Device | Depression Subscale From the Hospital Anxiety and Depression Scale (HADS) | 20 weeks | 7.50 Units on a scale | Standard Deviation 1.05 |
| Inactive Device | Depression Subscale From the Hospital Anxiety and Depression Scale (HADS) | 10 weeks | 10.11 Units on a scale | Standard Deviation 1.05 |
| Inactive Device | Depression Subscale From the Hospital Anxiety and Depression Scale (HADS) | 20 weeks | 9.75 Units on a scale | Standard Deviation 2.25 |
Comparison: A power analysis was conducted with G\*Power, specifying a standard Type I error (α = .05) and desired power of .80. Results indicated that a total sample of 26 would be sufficient. Below are the results of the intent-to-treat analysis. Patients that did not complete the assessment after the blinded phase had their baseline scores carried forward. Post-intervention depression scores were regressed on pre-intervention depression scores and condition, using an ANCOVA model.p-value: 0.18ANCOVA
Comparison: Below are the results of the per protocol analysis. Patients that did not complete the assessment after the blinded phase had their baseline scores carried forward. Post-intervention depression scores were regressed on pre-intervention depression scores and condition, using an ANCOVA model.p-value: 0.25ANCOVA
Secondary
Number of Headache Days Collected From the Migraine Disability Assessment (MIDAS).
Participants are asked to indicate the number of days in the last 3 months during which they experienced a headache. If a headache lasted more than 1 day, they are instructed to count each day. Scores are expected between 0-90 with higher numbers corresponding to a greater number of headache days.
Time frame: 10 and 20 weeks
Population: The 10-week measure includes only those individuals who completed the blinded phase of the study. The 20-weel measure includes only those individuals who completed the open label phase of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VNS Device | Number of Headache Days Collected From the Migraine Disability Assessment (MIDAS). | 10 weeks | 4.10 Days | Standard Deviation 6.76 |
| VNS Device | Number of Headache Days Collected From the Migraine Disability Assessment (MIDAS). | 20 weeks | 6.29 Days | Standard Deviation 10.63 |
| Inactive Device | Number of Headache Days Collected From the Migraine Disability Assessment (MIDAS). | 10 weeks | 13.78 Days | Standard Deviation 23.49 |
| Inactive Device | Number of Headache Days Collected From the Migraine Disability Assessment (MIDAS). | 20 weeks | 14.25 Days | Standard Deviation 25.58 |
Comparison: A power analysis was conducted with G\*Power, specifying a standard Type I error (α = .05) and desired power of .80. Results indicated that a total sample of 26 would be sufficient. Below are the results of the intent-to-treat analysis. Patients that did not complete the assessment after the blinded phase had their baseline scores carried forward. Post-intervention headache days was regressed on pre-intervention headache days and condition, using an ANCOVA model.p-value: 0.58ANCOVA
Comparison: Below are the results of the per protocol analysis. Patients that did not complete the assessment after the blinded phase had their baseline scores carried forward. Post-intervention headache days was regressed on pre-intervention headache days and condition, using an ANCOVA model.p-value: 0.49ANCOVA
Secondary
Patient Global Improvement of Change (PGIC)
PGIC is a 7-point scale used to quantify a patient's rating of overall improvement. Patients rate their change from 1 (no change or gotten worse) to 7 (considerable improvement). Higher scores indicate greater improvement since starting the intervention.
Time frame: 10 and 20 weeks
Population: The 10-week measure includes only those individuals who completed the blinded phase of the study. The 20-weel measure includes only those individuals who completed the open label phase of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VNS Device | Patient Global Improvement of Change (PGIC) | 10 weeks | 4.00 Score on a scale | Standard Deviation 2.06 |
| VNS Device | Patient Global Improvement of Change (PGIC) | 20 weeks | 3.71 Score on a scale | Standard Deviation 1.98 |
| Inactive Device | Patient Global Improvement of Change (PGIC) | 10 weeks | 3.11 Score on a scale | Standard Deviation 1.9 |
| Inactive Device | Patient Global Improvement of Change (PGIC) | 20 weeks | 5.37 Score on a scale | Standard Deviation 1.41 |
Comparison: A power analysis was conducted with G\*Power, specifying a standard Type I error (α = .05) and desired power of .80. Results indicated that a total sample of 26 would be sufficient. Below are the results of the intent-to-treat analysis. Patients that did not complete the assessment after the blinded phase were assigned a score of 1 indicating no change in their condition. Post-intervention PGIC scores were compared between conditions.p-value: 0.23t-test, 2 sided
Comparison: Below are the results of the per protocol analysis. Post-intervention PGIC scores were compared between conditions.p-value: 0.23t-test, 2 sided
Secondary
Physical Function Subscale From the Short Form Health Survey (SF-36)
A normalized indicator of physical functioning with a range from 0-100. Higher scores indicate fewer limitations to activity.
Time frame: 10 and 20 weeks
Population: The 10-week measure includes only those individuals who completed the blinded phase of the study. The 20-weel measure includes only those individuals who completed the open label phase of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VNS Device | Physical Function Subscale From the Short Form Health Survey (SF-36) | 10 weeks | 65.50 Score on a scale | Standard Deviation 19.78 |
| VNS Device | Physical Function Subscale From the Short Form Health Survey (SF-36) | 20 weeks | 60.71 Score on a scale | Standard Deviation 32.97 |
| Inactive Device | Physical Function Subscale From the Short Form Health Survey (SF-36) | 10 weeks | 55.56 Score on a scale | Standard Deviation 24.81 |
| Inactive Device | Physical Function Subscale From the Short Form Health Survey (SF-36) | 20 weeks | 56.25 Score on a scale | Standard Deviation 27.35 |
Comparison: A power analysis was conducted with G\*Power, specifying a standard Type I error (α = .05) and desired power of .80. Results indicated that a total sample of 26 would be sufficient. Below are the results of the intent-to-treat analysis. Patients that did not complete the assessment after the blinded phase had their baseline scores carried forward. Post-intervention physical function scores was regressed on pre-intervention physical function and condition, using an ANCOVA model.p-value: 0.13ANCOVA
Comparison: Below are the results of the per protocol analysis. Patients that did not complete the assessment after the blinded phase had their baseline scores carried forward. Post-intervention physical function scores was regressed on pre-intervention physical function and condition, using an ANCOVA model.p-value: 0.12ANCOVA