Effects of Botanical Microglia Modulators in Gulf War Illness

Study Overview
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Brief Summary
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The overall objective of this protocol is to test if Gulf War Illness (GWI) involves chronic inflammation that cannot be measured with typical techniques. The investigators will be observing the effects of nine different botanical compounds (supplements) that are known to suppress inflammation. If one of those supplements helps the symptoms of GWI, it will give the investigators information about what is wrong in people with GWI.

Detailed Description
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There is still a poor understanding of the pain, fatigue, and other symptoms that affect approximately 250,000 veterans. The precise mechanism of Gulf War Illness (GWI) is not understood, and there is no targeted treatment for the condition. A current model for GWI points to the central nervous system, immune cells, called microglia that may be hyperactive in patients with GWI. Discovering effective treatments for this disorder is a top priority of GWI research. Given the investigator's preliminary data, it is suspected that GWI is a form of low-level neuroinflammation that involves hypersensitivity of receptors on microglia. In order to help test that hypothesis, the investigators will be administering supplements that have been shown in vitro or animal in vivo to suppress microglia function in a way that is anti-inflammatory and neuroprotective. If any of these agents suppress symptoms in GWI, it will give the investigators important information about the disease that may allow for creation of better diagnostic tools and treatments in future research studies. Observing the effects of the selected nine anti-inflammatory botanical compounds, in this clinical study, is a strong compliment to the ongoing mechanistic GWI research.

Official Title
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Effects of Botanical Microglia Modulators in Gulf War Illness

Conditions
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Gulf War Illness

Intervention / Treatment
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* Dietary Supplement: Boswellia Serrata
* Dietary Supplement: Curcumin
* Dietary Supplement: Epimedium
* Dietary Supplement: Fisetin
* Dietary Supplement: Luteolin
* Dietary Supplement: Nettle
* Dietary Supplement: Pycnogenol
* Dietary Supplement: Reishi Mushroom
* Dietary Supplement: Resveratrol
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male Age 39-65, inclusive Veterans who meet the Kansas inclusion criteria for GWI Present in Persian Gulf between 1990 and August 1991 Patient completes daily report during 2 week baseline period (at least 80% completion rate) Able to receive a venous blood draw Exclusion Criteria: Positive rheumatoid factor at screening Positive anti-nuclear antibody at screening C-reactive protein> 3mg/L at screening Erythrocyte Sedimentation Rate> 40mm/hr at screening Auto-immune disorder Diagnosed Rheumatologic Condition Major PTSD symptoms Hypotension (under 90/60 mm Hg) or history of cardiovascular disease Antihypertensive, anticoagulant medication, nitroglycerine, lithium medication use Diabetes with Hemoglobin A1C >9% History of anaphylaxis to study botanical compounds Current daily use of opioid medication Hospital Anxiety and Depression Scale, Depression subscale score of 16 or higher at baseline Current litigation of worker's compensation claim Blood or clotting disorder Acute infection (body temperature over 100 degrees F) Current daily use of confounding-anti-inflammatory medication as part of regular medication regimen Individuals that are not able to read & understand English

Ages Eligible for Study
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Minimum Age: 39 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Boswellia Serrata<br>400-800mg in capsule form by mouth every day | Dietary Supplement: Boswellia Serrata<br> <br> * Other names: Indian frankincense;|
| Experimental: Curcumin<br>1000-2000mg in capsule form by mouth every day | Dietary Supplement: Curcumin<br> <br> * Other names: Meriva;|
| Experimental: Epimedium<br>1000-2000mg in capsule form by mouth every day | Dietary Supplement: Epimedium<br> <br> * Other names: Yin Yang Huo;|
| Experimental: Fisetin<br>200-800mg in capsule form by mouth every day | Dietary Supplement: Fisetin<br> <br> |
| Experimental: Luteolin<br>200-400mg in capsule form by mouth every day | Dietary Supplement: Luteolin<br> <br> |
| Experimental: Nettle<br>435-1305mg in capsule form by mouth every day | Dietary Supplement: Nettle<br> <br> * Other names: Stinging Nettle;|
| Experimental: Pycnogenol<br>200-400mg in capsule form by mouth every day | Dietary Supplement: Pycnogenol<br> <br> * Other names: Pine Bark Extract;|
| Experimental: Reishi Mushroom<br>1600-3200mg in capsule form by mouth every day | Dietary Supplement: Reishi Mushroom<br> <br> |
| Experimental: Resveratrol<br>200-600mg in capsule form by mouth every day | Dietary Supplement: Resveratrol<br> <br> * Other names: Red Wine Extract;|
| Placebo Comparator: Placebo<br>in capsule form by mouth every day | Dietary Supplement: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in overall Gulf War Illness disease severity | Self reported Gulf War Illness symptom severity reported twice daily, in the morning and evening, for the duration of the study. Single item scored 0-100 (0=no symptoms; 100=severe symptoms). | Average disease severity during the last two weeks of each treatment, compared to average severity during the last two weeks of placebo, as well as baseline. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Pain Severity | Self reported pain severity reported twice daily, in the morning and evening, for the duration of the study. Single item scored 0-100 (0=no pain; 100=severe pain). | Average pain severity during the last two weeks of each treatment, compared to average severity during the last two weeks of placebo, as well as baseline. | 
| Change from baseline in Fatigue Severity | Self reported fatigue severity reported twice daily, in the morning and evening, for the duration of the study. Single item scored 0-100 (0=not fatigued at all; 100=severely fatigued). | Average fatigue severity during the last two weeks of each treatment, compared to average severity during the last two weeks of placebo, as well as baseline. | 
| Change from baseline in Cognitive Symptom Severity | Self reported cognitive symptom severity reported twice daily, in the morning and evening, for the duration of the study. Single item scored 0-100 (0=not [able to think and remember] clearly at all; 100=[able to think and remember] very clearly). | Average cognitive symptom severity during the last two weeks of each treatment, compared to average severity during the last two weeks of placebo, as well as baseline. | 
| Change from baseline in Mood Symptom Severity | Self reported mood symptom severity reported twice daily, in the morning and evening, for the duration of the study. Single item scored 0-100 (0=not good [mood] at all; 100=extremely good [mood]). | Average mood severity during the last two weeks of each treatment, compared to average severity during the last two weeks of placebo, as well as baseline. | 
| Change from baseline in Dermatological Symptom Severity | Self reported dermatological symptom severity reported twice daily, in the morning and evening, for the duration of the study. Single item scored 0-100 (0=no skin problems at all; 100=severe skin problems). | Average dermatological symptom severity during the last two weeks of each treatment, compared to average severity during the last two weeks of placebo, as well as baseline. | 
| Change from baseline in Respiratory Symptom Severity | Self reported respiratory symptom severity reported twice daily, in the morning and evening, for the duration of the study. Single item scored 0-100 (0=no breathing or respiratory problems at all; 100=severe breathing or respiratory problems). | Average respiratory symptom severity during the last two weeks of each treatment, compared to average severity during the last two weeks of placebo, as well as baseline. | 
| Change from baseline in Gastrointestinal Symptom Severity | Self reported gastrointestinal symptom severity reported twice daily, in the morning and evening, for the duration of the study. Single item scored 0-100 (0=no bowel or GI problems at all; 100=severe bowel or GI problems). | Average gastrointestinal symptom severity during the last two weeks of each treatment, compared to average severity during the last two weeks of placebo, as well as baseline. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gulf War Syndrome, Chronic Multisymptom Illnesses, Medically Unexplained Illnesses