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| ID | Type | Description | Link |
|---|---|---|---|
| 2025P011630 | Other Identifier | Emory IRB | |
| CDMRP-TX240208 | Other Grant/Funding Number | Congressionally Directed Medical Research Programs (CDMRP) | |
| CDMRP-TX240208P1 | Other Grant/Funding Number | Congressionally Directed Medical Research Programs (CDMRP) |
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| Name | Class |
|---|---|
| Congressionally Directed Medical Research Programs | FED |
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The main goal of the proposed study is to critically evaluate a nonpharmacological and readily available therapy, cranial electrical stimulation (CES) using Alpha-Stimâ„¢, and to discover the brain function mechanisms underlying Gulf War Illness-related Headache and Pain (GWI-HAP) and treatment response to CES.
For this objective, the investigators will employ an adaptive trial design as well as a neuroimaging technique using MRI, which has become the pre-eminent technique for assessing the integrity of brain function, connectivity, and organization in healthy brain and pathology.
Gulf War Veterans are disproportionately plagued by fibromyalgia-like symptoms including headaches, joint, and muscle pain, known as gulf war illness pain or GWI-HAP. Treatment options are limited, and the neurobiology of these symptoms is poorly understood.
In this population, the investigators plan to test a portable, non-pharmacological, non-invasive therapy (Alpha-Stimâ„¢) that is FDA-cleared for anxiety, insomnia, and pain, and readily available for widespread implementation in the United States. This cranial electrical stimulation (CES) device has shown promising, though limited results for anxiety, insomnia, and pain. They also plan to employ magnetic resonance spectroscopy (MRS) to evaluate neuroinflammation.
Subjects will be male and females, age 40-80 years old, with a diagnosis of Gulf war illness. Subjects will be recruited by referral and posted flyers on Emory campus, ResearchMatch, the Gulf War Registry, and the Wounded Warriors' Program. The research team will not approach vulnerable populations including minors, prisoners, pregnant persons, neonates or human fetuses, wards of the state, or cognitively impaired persons. Recruitment, screening and enrollment will occur at the Emory clinics (EUHM and EUH) and the Human Subjects Research Building II.
This randomized, double-blind, sham-controlled study will compare the efficacy of "active" or true CES therapy to "sham" CES therapy. Participants will be randomized in a 1:1 ratio to true or sham CES (n=104 total; 52 true, 52 sham). Up to 130 subjects will be enrolled to achieve 104 treated subjects. Baseline assessments including quality of life questionnaires and pain assessments, in addition to MRI will be obtained prior to initiation of the intervention.
The participant will be trained in device usage and instructed to use the device each evening around the same time for 60 minutes (timer will be pre-set). They will also be provided detailed instructions.
The intervention (both sham and true CES) will occur over the course of 6 weeks, and participants will be assessed again post-treatment. To assess our neuroimaging outcomes, MRI will also be obtained at 6 weeks post-treatment, to assess for changes in connectivity and neuroinflammation. The total time commitment for most subjects will be 7 weeks.
Participants who are initially randomized to sham and are determined to be non-responders (<2 point decrease on DVPRS) will be offered the opportunity to utilize the true CES therapy with additional reimbursement and follow-up periods. They will use the device for an additional 6 weeks and return for post-treatment follow up at that time (12 weeks after initial therapy) that will include additional MRI and the original baseline and 6-week assessments. The total time commitment for these subjects will be 13 weeks.
A verbal prescreening consent will be used to confirm eligibility. Informed consent will be conducted in person with the participant and written, or over the telephone or zoom with consent signed using Hipaa Part 11 compliant DocuSign. Participants may also consent to be contacted for future research.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| True CES therapy | Experimental | The participant will be trained in device usage and instructed to use the device each evening around the same time for 60 minutes (timer will be pre-set). The intervention (true CES) will occur over the course of 6 weeks. |
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| Sham CES therapy | Sham Comparator | The participant will be trained in device usage and instructed to use the device each evening around the same time for 60 minutes (timer will be pre-set). The intervention (sham CES) will occur over the course of 6 weeks. |
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| True CES therapy for non-responders | Experimental | For the non-responders (<2 point decrease on DVPRS), the blind will be broken, and those non-responder participants who were initially assigned to sham placebo CES during the first 6 weeks of the intervention, now will be offered the opportunity to utilize the true CES device in a modified sequential parallel comparison design for an additional 6 weeks. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cranial electrical/electrotherapy stimulation (CES) | Device | Cranial electrical/electrotherapy stimulation (CES) is a non-pharmacological, portable, non-invasive intervention. Active research units will be locked at the specified amplitude and administer that amplitude of stimulation for 60 minutes therapy. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Defense and Veterans Pain Rating Scale (DVPRS) from baseline | The Defense and Veterans Pain Rating Scale (DVPRS) is a pain assessment tool. Patients will rate their pain intensity on a scale of 0 to 10, where 0 is no pain and 10 is the worst imaginable pain. | Baseline, 6 and 12 weeks post-intervention |
| Change in Brief Pain Inventory (BPI) severity subscale from baseline | The BPI assesses pain severity and interference with function. The pain severity subscale consists of 4 items, each rated on a 0-10 numerical scale (0 = "no pain," 10 = "pain as bad as you can imagine"). Scores are averaged to yield a total range of 0-10. Lower scores reflect less severe pain and are considered favorable outcomes. | Baseline, 6 and 12 weeks post-intervention |
| Change in Brief Pain Inventory (BPI) pain interference subscale from baseline | The pain interference subscale consists of 7 items rated on a 0-10 numerical scale (0 = "does not interfere," 10 = "completely interferes"), assessing the impact of pain on daily activities such as mood, walking ability, work, and enjoyment of life. Scores are averaged to create a total range of 0-10. Lower scores reflect less interference from pain and are considered favorable outcomes. | Baseline, 6 and 12 weeks post-intervention |
| Measure | Description | Time Frame |
|---|---|---|
| Change in sit-to-stand/chair stand test | It involves repeatedly standing up and sitting down from a chair for a set period (30 seconds). The number of complete repetitions within the time limit is recorded. | Baseline, 6 and 12 weeks post-intervention |
| Change in bicep(arm) curls |
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Inclusion Criteria:
Subjects must be male and female age 40-80 years old
Meet criteria for GWVI based on the CDC and Kansas Criteria for GWVI.
Subjects must self-report consistent, daily pain (greater than or equal to 4 on the DVPRS) >90 days (prior to enrollment)
Subjects must have intact skin free of infection at the site of electrode placement (earlobe).
Subjects must be willing to participate and understand the consent.
Subjects must be right-handed to provide consistency in brain structure and function.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Katherine Egan, RN, CCRC | Contact | 404-727-8463 | kfegan@emory.edu |
| Name | Affiliation | Role |
|---|---|---|
| Anna Woodbury, MD, MSc | Emory University 404-727-8463 | Principal Investigator |
| Lisa C Krishnamurthy, PhD | Emory University 404-712-5332 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Emory Clinic | Recruiting | Atlanta | Georgia | 30307 | United States |
Neuroimaging data (de-identified) will be shared for use in ENIGMA as part of the Chronic Pain Working Group Clinical outcomes (de-identified) for correlation with neuroimaging data Data may also be shared with the DOD and with other investigators
September 1, 2030-September 1, 2032
- Data will be shared including with: DOD ENIGMA Chronic Pain Working Group Device manufacturer for the CES in case they would like to apply for an FDA indication
- For the following type of analyses: Neuroimaging analysis Analysis of clinical outcomes
- Through a data usage agreement
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| ID | Term |
|---|---|
| D018923 | Persian Gulf Syndrome |
| D010146 | Pain |
| ID | Term |
|---|---|
| D009784 | Occupational Diseases |
| D000067398 | War-Related Injuries |
| D014947 | Wounds and Injuries |
| D009461 | Neurologic Manifestations |
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randomized, double-blind, sham-controlled clinical trial
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| Sham Cranial electrical/electrotherapy stimulation (CES) | Device | Sham research units will be locked into active sham mode which provides stimulation designed to provide the sensation of stimulation for only 5 minutes while continuing to count down for the remaining 55 minutes. |
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The test involves having the individual perform as many controlled arm curls as possible within a 30-second timeframe. The total number of controlled repetitions within the 30-second period is recorded. |
| Baseline, 6 and 12 weeks post-intervention |
| Change in handgrip strength | Involves using a hand-held dynamometer to measure the maximum force exerted when squeezing the device. Maximun strength will be recorded. | Baseline, 6 and 12 weeks post-intervention |
| Change in finger-tap test | The Finger Tapping Test (FTT) is a physical function assessment used to evaluate motor speed and coordination. It's a simple test where a person taps their index finger against their thumb as quickly as possible for a set period, often 10 seconds, and the number of taps is recorded. | Baseline, 6 and 12 weeks post-intervention |
| Change in Patient-Reported Outcomes Measurement Information System (PROMIS): sleep score | This measure focuses on the past seven days and assesses perceived difficulties with sleep onset, sleep continuity, and overall sleep quality. It includes a 5-point Likert scale (1=never to 5=always) for each item. Raw scores are summed, and then converted to T-scores, where 50 represents the average for the U.S. general population, and a standard deviation of 10. Higher T-scores represent better health. | Baseline, 6 and 12 weeks post-intervention |
| Change in PROMIS: social isolation score | This measure focuses on the past seven days and assesses perceived difficulties with social isolation. The measure use a 5-point Likert scale (1=never to 5=always) for a total of 4 items item. Total possible score range from 4-20 with lower score correlating with better study outcome. | Baseline, 6 and 12 weeks post-intervention |
| Change in PROMIS: alcohol use score | This measure focuses on the past seven days and assesses perceived difficulties with alcohol use. The measure use a 5-point Likert scale (1=never to 5=always) for a total of 37 items item. Total possible score range from 37-185 with lower score correlating with better study outcome. | Baseline, 6 and 12 weeks post-intervention |
| Change in PROMIS: global health score | This measure focuses on the past seven days and assesses perceived difficulties with global health. The measure use a 5-point Likert scale (1=never to 5=always) for a total of 9 items item. Total possible score range from 9-45 with lower score correlating with better study outcome. | Baseline, 6 and 12 weeks post-intervention |
| Change in PROMIS 29 score | PROMIS-29 involves assessing responses on a 1-5 scale (or 0-10 for pain intensity), then averaging responses within each of the seven health domains (physical function, fatigue, pain interference, depressive symptoms, anxiety, ability to participate in social roles and activities, and sleep disturbance) to create a raw score for that domain. These raw scores are transformed into T-scores, with a mean of 50 and a standard deviation of 10, to indicate health status relative to a reference population, where higher T-scores represent better health. | Baseline, 6 and 12 weeks post-intervention |
| Change in SF-36 score from baseline | SF-36 is a multi-purpose, short-form health survey developed for assessing health-related quality of life. It measures eight health concepts: physical functioning, role limitations due to physical health problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to personal or emotional problems, and mental health. Each scale score has a possible score range 0-100 scale, where 0 represents the worst possible health state and 100 represents the best. The scores for the items that contribute to each scale are averaged to produce a total score for the scale (possible range 0-100), higher score represents better outcome. | Baseline, 6 and 12 weeks post-intervention |
| Change in Resting-State fMRI Connectivity measured with Seed-Based Functional Connectivity Analysis | This outcome assesses changes in functional connectivity within brain function networks relevant to chronic pathology through Pearson correlation between fMRI signal in relevant seed regions of interest. Higher FC within impaired brain function networks (e.g., fronto-temporal) and lower FC within abnormally enhanced (pain expression) represent better outcomes. | Baseline, 6 and 12 weeks post-intervention |
| Change in Resting-State fMRI Connectivity measured with Independent Components Analysis | This outcome assesses changes in functional connectivity within the brain and between brain function networks relevant to chronic pathology. Independent Components Analysis (ICA) measures resting state network (IC) connectivity strength (expressed as z-sore) and between functional network connectivity (FNC). Higher IC strength within impaired brain function networks (e.g., fronto-temporal) and lower IC strength within abnormally enhanced (pain expression) represent better outcomes. Higher FNC in beneficent inter-network connections (e.g., between fronto-striatal and limbic networks) and lower FNC in malignant inter-network connections (e.g., default mode and pain expression networks) represent better outcomes. | Baseline, 6 and 12 weeks post-intervention |
| Change in Magnetic Resonance Spectroscopy Metabolite: lactate | This outcome assesses changes in brain neurochemical composition across the study period. Magnetic Resonance Spectroscopy (MRS) will be used to measure water-scaled, tissue-corrected concentrations of lactate. Reductions in lactate represents better outcome. | Baseline, 6 and 12 weeks post-intervention |
| Change in Magnetic Resonance Spectroscopy Metabolite: N-acetyl aspartate (NAA) | Magnetic Resonance Spectroscopy (MRS) will be used to measure water-scaled, tissue-corrected concentrations of N-acetyl aspartate (NAA). Reductions in NAA represents better outcome. | Baseline, 6 and 12 weeks post-intervention |
| Change in Magnetic Resonance Spectroscopy Metabolite: choline | Magnetic Resonance Spectroscopy (MRS) will be used to measure water-scaled, tissue-corrected concentrations of choline. Reductions in choline represent better outcome. | Baseline, 6 and 12 weeks post-intervention |
| Change in Magnetic Resonance Spectroscopy Metabolite: tCr | Magnetic Resonance Spectroscopy (MRS) will be used to measure water-scaled, tissue-corrected concentrations of total creatine (tCr). A decrease in tCr concentration, represents better outcome. | Baseline, 6 and 12 weeks post-intervention |
| Change in Magnetic Resonance Spectroscopy Metabolites: Ratio of NAA/tCr | Ratio of NAA/tCr will also be quantified, as a decreased ratio of NAA/tCr has been linked to mitochondrial dysfunction in ill Gulf War Veterans. An increase in NAA/tCr ratio, represents better outcome. | Baseline, 6 and 12 weeks post-intervention |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |