Gulf War IllnessPhase 1E/MNCT04254627
TNF and Glucocorticoid Antagonist for GWI Associated Multi-symptom Disease Homeostasis Reset
A Phase 1 study testing Etanercept and Mifepristone in people with Gulf War Illness, run by Nova Southeastern University at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 45 to 70 years, men only
- Conditions the study is for
- Gulf War Illness
- What is being tested?
- Etanercept and Mifepristone
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 2 sitesUnited States
- Study dates
- 24 Sep 2021to 30 Sep 2025
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 to 70 years
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 45-70 years old,
- Male sex,
- In good health by medical history prior to 1990
- 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:
- Fatigue after exercise as predominant component (a history of exercise intolerance or exercise-induced worsening of symptoms)
- 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.
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- 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.
- Able to provide consent to study,
- Subjects of childbearing potential must practice effective contraception during the study, and be willing to continue contraception for at least 6 months after intervention.
- Agrees to participate in follow-up visits.
Who cannot join
- 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)
- Known allergy to mifepristone, misoprostol, or medicines that contain misoprostol, such as Cytotec or Arthrotec.
- 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.
- Current organ failure (as determined by metabolic panel and self-report)
- 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
- Chronic active infections such as HIV, hepatitis B, and hepatitis C (as determined by antibody tests
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- History of organ transplant (self-report)
- Current untreated primary sleep disorders such as insomnias, sleep related breathing disorders, etc. (self-report)
- History of tuberculosis exposure (determined by QuantiFERON-TB® positivity)
- Use of medications that could affect immune function (e.g., steroids, immunosuppressants) or limit the interpretation of the exercise challenge (self- report)
- Renal disease (self-report; laboratory results: renal insufficiency with serum creatinine > 2.0 mg/dL or eGFR < 44; or currently on renal dialysis).
- 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.
- Currently have no exclusionary diagnoses that could reasonably explain the symptoms of their fatiguing illness and their severity, using the exclusion criteria best described in the Ambiguities in case definition paper for Chronic Fatigue Syndrome (CFS) which clarifies exclusionary conditions.
- Are scheduled for surgery within 24 weeks of study enrollment.
- Cushing's disease or salivary cortisol level greater than 0.812 ug/dL.
- QT prolongation, as evidenced by medical history (self-report) or ECG at screening.
- Uncontrolled diabetes (A1c>7.5).
- Prohibited concomitant or prior therapies:
- Immunosuppressant drugs, including glucocorticoid taper, topical/inhaled glucocorticoids
- Currently on dialysis
- Recipient of bone marrow or organ transplant
- Previous or current treatment with angiogenic growth factors, cytokines, gene or stem cell therapy
- Participating in another interventional clinical trial of an investigational therapy within 8 weeks prior to consent to participate in this study, or planning to participate in another interventional clinical trial of an investigational therapy within 26 weeks after consent to participate in this study
- Any herbal medicine that contains licorice root.
- Selective Blood thinners:
- Only Apixaban and Warfarin will be included. Rivaroxaban cannot be included as there are higher drug to drug interactions as well as Apixaban 2.5 mg BID.
- If a participant is on Warfarin, a baseline INR will be obtained, the Warfarin dose will be reduced and an INR will be rechecked 48-72 hours after starting Mifepristone.
- If a participant is on Apixaban, the dose must be reduced by 50%.
- Please note that if participants are taking anticoagulants, there is a potential interaction that could lead to possible increased on risk of bleeding and will require more frequent monitoring by the Coordinator.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Nova Southeastern University
Davie, Florida, 33314
Miami VA Healthcare System
Miami, Florida, 33125
About this study
Official title: Tumor Necrosis Factor (TNF) and Glucocorticoid Antagonist for Gulf War Illness (GWI)-Associated Multi-symptom Disease Homeostasis Reset
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.
Read the 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.
- Conditions
- Gulf War Illness
- Being tested
- Etanercept, Mifepristone
- Keywords
- Gulf War Illness, Veterans, etanercept, mifepristone, VA Healthcare, TNF, Multi-symptom disease, Phase I
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EtanerceptDrug
Also called Enbrel
Etanercept 50 mg weekly injection
MifepristoneDrug
Also called Mifeprex, RU-486
Mifepristone 300 mg pill
| Study group | Role | What they receive |
|---|---|---|
| Mifepristone 300 mg | Experimental | All participants will receive etanercept 50 mg weekly for 12 weeks. After completion of the etanercept course, participants will be randomized between two Arms of mifepristone. Participants randomized to Arm 1 will receive one week of mifepristone at 300 mg daily. Receives: Drug: Etanercept; Drug: Mifepristone |
| Mifepristone 600 mg | Experimental | All participants will receive etanercept 50 mg weekly for 12 weeks. After completion of the etanercept course, participants will be randomized between two Arms of mifepristone. Participants randomized to Arm 2 will receive one week of mifepristone at 600 mg (2x300 mg) daily. Receives: Drug: Etanercept; Drug: Mifepristone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety - incidence and severity of adverse events
Safety is assessed by the incidence and severity of adverse events, by relation to the study intervention.
Measured: 16 weeks
Mechanistic effects on biomarker relationships
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.
Measured: Baseline and 24 weeks
Secondary outcomes (1)
Homeostatic network correction
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.
Measured: Baseline and 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Feb 2020
- Study start24 Sep 2021
- Primary completion30 Sep 2025
- Study completion30 Sep 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Gulf War IllnessStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Nova Southeastern University
- Sponsor type
- University, hospital or other
- Collaborators
- RTI International, Miami VA Healthcare System
- Responsible party
- Sponsor
- Investigators
- Nancy Klimas, MD, Principal investigator, Miami VA Healthcare System
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04254627
- Sponsor's protocol ID
- GWICTIC-EMphase1
- Other IDs
- CDMRP-PC16GW170044
- Acronym
- E/M
- Status last verified
- Jun 2026
- First submitted
- 9 Jan 2020
- Last updated
- 18 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: The plan is to release primary results from the study to ClinicalTrials.gov. Data are the property of Nova Southeastern University, but data and publication thereof will not be unduly withheld. Those interested in E/M data should reach out to Nancy Klimas (PI) for more information.
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Tumor Necrosis Factor (TNF) and Glucocorticoid Antagonist for Gulf War Illness (GWI)-Associated Multi-symptom Disease Homeostasis Reset
- ClinicalTrials.gov ID
- NCT04254627
- Acronym / sponsor ID
- E/M / GWICTIC-EMphase1
- Conditions
- Gulf War Illness
- Keywords
- Gulf War Illness, Veterans, etanercept, mifepristone, VA Healthcare, TNF, Multi-symptom disease, Phase I
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Nova Southeastern UniversityUniversity, hospital or other
- Collaborators
- RTI International, Miami VA Healthcare System
- Study start
- 24 Sep 2021 (actual)
- Primary completion
- 30 Sep 2025 (actual)
- Study completion
- 30 Sep 2025 (actual)
- First posted
- 5 Feb 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Mifepristone 300 mg | Experimental | Drug: Etanercept, Drug: MifepristoneAll participants will receive etanercept 50 mg weekly for 12 weeks. After completion of the etanercept course, participants will be randomized between two Arms of mifepristone. Participants randomized to Arm 1 will receive one week of mifepristone at 300 mg daily. |
| Mifepristone 600 mg | Experimental | Drug: Etanercept, Drug: MifepristoneAll participants will receive etanercept 50 mg weekly for 12 weeks. After completion of the etanercept course, participants will be randomized between two Arms of mifepristone. Participants randomized to Arm 2 will receive one week of mifepristone at 600 mg (2x300 mg) daily. |
Who may qualify
- Ages
- 45 to 70 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 45-70 years old,
- Male sex,
- In good health by medical history prior to 1990
- 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:
- Able to provide consent to study,
Key exclusion criteria (29 listed)
- 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)
- Known allergy to mifepristone, misoprostol, or medicines that contain misoprostol, such as Cytotec or Arthrotec.
- 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.
- Current organ failure (as determined by metabolic panel and self-report)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EtanerceptAlso: EnbrelEtanercept 50 mg weekly injection | Drug | Mifepristone 300 mg, Mifepristone 600 mg |
| MifepristoneAlso: Mifeprex, RU-486Mifepristone 300 mg pill | Drug | Mifepristone 300 mg, Mifepristone 600 mg |
Primary outcome
Safety - incidence and severity of adverse events
Time frame: 16 weeks
Safety is assessed by the incidence and severity of adverse events, by relation to the study intervention.
Mechanistic effects on biomarker relationships
Time frame: 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.
1 secondary outcome
Homeostatic network correction
Time frame: Baseline and 24 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2026.
- Individual participant dataSharing planned: No. The plan is to release primary results from the study to ClinicalTrials.gov. Data are the property of Nova Southeastern University, but data and publication thereof will not be unduly withheld. Those interested in E/M data should reach out to Nancy Klimas (PI) for more information.
Related trials for Gulf War Illness
RecruitingObservational study
NIH Investigative Deep Phenotyping Study of Gulf War Veteran Health (Project NIH IN-DEPTH)
Gulf War Illness
RecruitingPhase 2
Ca-Mg Butyrate in Gulf War Illness
Gulf War Illness, Chronic Fatigue
Not yet recruiting
Pycnogenol (French Maritime Pine Bark) for the Treatment of Gulf War Illness
Gulf War Syndrome
RecruitingPhase 1
Clinical Evaluation of Montelukast in Veterans With Gulf War Illness
Gulf War Syndrome
Recruiting
Mechanisms of Gulf War Illness
Gulf War Illness, Irritable Bowel Syndrome
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nancy Klimas, MD principal investigator
Miami VA Healthcare System
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Etanercept and Mifepristone in people with Gulf War Illness, run by Nova Southeastern University at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety - incidence and severity of adverse events (time frame: 16 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2026.