Gulf War Illness
Conditions
Keywords
Gulf War Illness, Veterans, etanercept, mifepristone, VA Healthcare, TNF, Multi-symptom disease, Phase I
Brief summary
Gulf War Illness is a condition that affects multiple major organ systems, resulting in a diverse array of symptoms that include debilitating fatigue, memory and cognition difficulties, headaches, sleep disturbances, gastrointestinal problems, skin rashes, and musculoskeletal/joint pain. This phase I single-site, open-label two-arm study will assess the safety and mechanistic efficacy of a sequential etanercept-mifepristone intervention for Gulf War Illness. The results of this phase I study will be compared to those from an existing short-duration study to identify the optimal duration and dosage for use in a future phase II study.
Detailed description
This is a study in male Veterans 45-70 years of age who meet the modified Kansas and Centers for Disease Control and Prevention (CDC) criteria for GWI (Gulf War Illness) and have high physiologic stress. This phase I single-site, open-label, two-arm study will focus on optimizing the dosage of a sequential etanercept-mifepristone intervention for GWI. Twenty participants will be assessed at baseline, 6, 12, 13, 16 and 24 weeks. The investigators will use systems biology methods to perform computational modelling of physiological responses to supervised maximal exercise challenge studies on a fitness bicycle at baseline and 24 weeks. These analyses will assess the impact of the treatment on homeostatic networks: the changes in levels of physiological parameters and the changes in inter-correlations among the measured parameters (e.g., cytokines), cross-sectionally and over time. Participants will also undergo subjective assessments of functional health, symptom severity, pain, fatigue, and cognition at baseline, 6, 12, 13, 16, and 24 weeks. Participants will be observed through the treatment period and for 3 months after completion to assess immediate effects and durability of the response. The results of this phase I study will be compared to those from an existing short-duration study to identify the optimal duration and dosage for use in a future phase II study.
Interventions
DRUGEtanercept
Etanercept 50 mg weekly injection
DRUGMifepristone
Mifepristone 300 mg pill
Sponsors
Nova Southeastern University
RTI International
Miami VA Healthcare System
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
45 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. 45-70 years old, 2. Male sex, 3. In good health by medical history prior to 1990 4. Meets modified Kansas and CDC case definition criteria for Gulf War Illness. Original Kansas criteria and CDC case definitions, including their exclusionary conditions. The modified Kansas definition, which includes the CDC criteria, includes the following: 1. Fatigue after exercise as predominant component (a history of exercise intolerance or exercise-induced worsening of symptoms) 2. Allowance for normal illnesses of aging, such as hypertension and diabetes, if the conditions are treated and are in demonstrable stable and normal ranges at the time of screening and assessment. 3. Allowance of stable comorbid conditions such as PTSD, MDD, and TBI that have not required hospitalization in the 5 years prior to recruitment. Severe TBI is excluded. 5. Able to provide consent to study, 6. Subjects of childbearing potential must practice effective contraception during the study, and be willing to continue contraception for at least 6 months after intervention. 7. Agrees to participate in follow-up visits.
Exclusion criteria
1. Current treated or untreated major depression with psychotic or melancholic features, schizophrenia, bipolar disorder, delusional disorders, dementias of any type, and alcoholism or drug abuse (as determined by self-report, SAGE-SR, and Ham-D) 2. Known allergy to mifepristone, misoprostol, or medicines that contain misoprostol, such as Cytotec or Arthrotec. 3. Current heavy alcohol or tobacco use (self-report). Alcohol consumption not to exceed approximately 15 drinks per week (with a drink defined as 12 oz beer, 5 oz wine, or 1.5 oz distilled spirits) and tobacco use not to exceed 20 cigarettes (or equivalent) per day. 4. Current organ failure (as determined by metabolic panel and self-report) 5. Current treated or untreated rheumatologic and inflammatory disorders, as determined by medical diagnosis of one or more of the following: osteoarthritis, rheumatoid arthritis (RA), lupus, spondyloarthropathies -- ankylosing spondylitis (AS) and psoriatic arthritis (PsA), Sjogren's syndrome, gout, scleroderma, infectious arthritis, and polymyalgia rheumatic 6. Chronic active infections such as HIV, hepatitis B, and hepatitis C (as determined by antibody tests 7. History of organ transplant (self-report) 8. Current untreated primary sleep disorders such as insomnias, sleep related breathing disorders, etc. (self-report) 9. History of tuberculosis exposure (determined by QuantiFERON-TB® positivity) 10. Use of medications that could affect immune function (e.g., steroids, immunosuppressants) or limit the interpretation of the exercise challenge (self- report) 11. Renal disease (self-report; laboratory results: renal insufficiency with serum creatinine \> 2.0 mg/dL or eGFR \< 44; or currently on renal dialysis). 12. Hepatic insufficiency (bilirubin \>2.5mg/dL or transaminases \>5x the ULN) Subjects with Gilberts syndrome are eligible for the study if other liver function tests are normal, regardless of bilirubin level. 13. Currently have no exclusionary diagnoses that could reasonably explain the symptoms of their fatiguing illness and their severity, using the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety - incidence and severity of adverse events | 16 weeks | Safety is assessed by the incidence and severity of adverse events, by relation to the study intervention. |
| Mechanistic effects on biomarker relationships | Baseline and 24 weeks | Mechanistic effects on biomarker network dynamics are measured by the change in median summary score for network-level distance between the Gulf War Illness biomarker profile at rest and model-predicted stable (healthy) states. These summary scores have a minimum value of zero and reflect the overall difference between the multidimensional relationships of the immune, autonomic, and neuroendocrine systems of ill participants at rest, relative to predicted values for stable (healthy) states. The analysis will be completed using the results of physical measures and biomarker assays performed on blood draws taken at rest prior to exercise challenges at baseline and 16 weeks. These include a Gulf War Illness-specific nanostring gene expression platform, an 18-multiplex cytokine assay, flow cytometry, neuropeptide, sex and stress hormone panels, and physical autonomic measures. Decreases in summary scores between baseline and 24 weeks indicate a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Homeostatic network correction | Baseline and 24 weeks | The degree of correction of the homeostatic network toward normal is measured by the median summary score for network-level differences in connectivity of biomarker networks at multiple times during dynamic exercise challenges. These summary scores have a minimum value of zero and reflect overall changes within the immune, autonomic, and neuroendocrine systems during exercise, relative to predicted values for stable (healthy) states. The analysis will use the results of physical measures and blood draws taken before, during, and after exercise challenges at baseline and 24 weeks. The biomarker assays and physical measures include a Gulf War Illness-specific nanostring gene expression platform, an 18-multiplex cytokine assay, flow cytometry, neuropeptide, sex and stress hormone panels, and physical autonomic measures at multiple times during each exercise challenge and 24 hours afterward. Decreases in summary scores between baseline and 16 weeks indicate a better outcome. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORNancy Klimas, MD
Miami VA Healthcare System
Outcome results
None listed