Etanercept + Mifepristone for Gulf War Syndrome

(E/M Trial)

Not currently recruiting at 1 trial location

Overseen By Amanpreet Cheema, PhD

Age: 18+

Sex: Male

Trial Phase: Phase 1

Sponsor: Nova Southeastern University

Must not be taking: Steroids, Immunosuppressants, Rivaroxaban, Licorice

Disqualifiers: Major depression, Schizophrenia, Bipolar, Alcoholism, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 13 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effects of two drugs, etanercept (a TNF receptor fusion protein) and mifepristone, for treating Gulf War Illness. This condition causes symptoms like severe tiredness, memory issues, headaches, and joint pain. Participants will receive etanercept for 12 weeks, followed by one of two different doses of mifepristone. The trial focuses on men who have experienced exercise-related fatigue and have other stable health conditions. The goal is to determine the optimal duration and dosage of these treatments for future studies. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but certain medications are prohibited. You cannot take immunosuppressants, glucocorticoids, or participate in another clinical trial. If you're on Warfarin or Apixaban, dosage adjustments are required. Herbal medicines with licorice root are also not allowed.

Will I have to stop taking my current medications?

The trial requires stopping certain medications that affect immune function, like steroids or immunosuppressants. If you're on blood thinners like Warfarin or Apixaban, the dose will need to be adjusted. It's best to discuss your specific medications with the trial coordinator.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that etanercept is generally safe and effective for treating conditions like rheumatoid arthritis and plaque psoriasis, meaning it is usually well-tolerated.

Studies involving patients with Cushing's syndrome found that some experienced serious side effects from mifepristone. Specifically, 31.9% of those taking mifepristone had serious side effects related to the treatment, compared to 4.7% of those taking a placebo. Mifepristone is also approved for other medical uses, suggesting a reliable safety record.

In this trial, participants will first receive etanercept, followed by mifepristone. Research indicates that both drugs have a reasonable safety profile, but like any treatment, there are risks. Participants should consider these findings and discuss them with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about etanercept and mifepristone for Gulf War Syndrome because these treatments offer a new approach compared to standard care, which often involves symptom management with medications like pain relievers and antidepressants. Etanercept works by targeting and reducing inflammation, potentially addressing one of the underlying causes of the syndrome. Meanwhile, mifepristone is being tested in two different doses (300 mg and 600 mg) for its potential to modulate the effects of stress hormones, which could help alleviate symptoms more effectively. This combination offers hope for directly tackling some of the root problems, rather than just managing symptoms.

What evidence suggests that this trial's treatments could be effective for Gulf War Syndrome?

Research has shown that etanercept, a medication often used for rheumatoid arthritis, might help reduce inflammation and symptoms of Gulf War Syndrome when combined with other treatments. Although specific data on etanercept for Gulf War Syndrome is limited, studies on other inflammatory conditions suggest it could relieve joint pain and fatigue. In this trial, all participants will receive etanercept for 12 weeks before randomization to different doses of mifepristone.

Mifepristone, which blocks stress hormones, has shown promise in improving memory and learning in Gulf War veterans. A controlled trial found that mifepristone improved mental performance, suggesting it might help with some cognitive symptoms of Gulf War Syndrome. Participants in this trial will be randomized to receive either 300 mg or 600 mg of mifepristone daily for one week.

Together, these treatments aim to address both inflammation and cognitive issues, offering a potential new approach for those experiencing the complex symptoms of Gulf War Syndrome. ^{1 2 6 7 8}

Who Is on the Research Team?

Nancy Klimas, MD

Principal Investigator

Miami VA Healthcare System

Are You a Good Fit for This Trial?

This trial is for male individuals aged 45-70 with Gulf War Illness, who were in good health before 1990 and meet specific illness criteria. They must not have severe comorbid conditions or a history of heavy alcohol/tobacco use. Participants should not have certain chronic infections, organ failure, or be on excluded medications like immunosuppressants.

Inclusion Criteria

I am between 45 and 70 years old.

I was in good health before 1990 according to my medical records.

My PTSD, depression, or brain injury is stable and hasn't needed hospital care in the last 5 years.

Exclusion Criteria

I have a diagnosed condition like arthritis, lupus, or another inflammatory disorder.

My fatigue is not explained by any other diagnosed conditions.

I have not used any treatments that are not allowed in this study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive etanercept 50 mg weekly for 12 weeks followed by mifepristone for 1 week

13 weeks

6 visits (in-person) at baseline, 6, 12, 13, 16, and 24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Etanercept
• Mifepristone

Trial Overview The study tests the safety and efficacy of Etanercept followed by Mifepristone to treat symptoms of Gulf War Illness. It's an early-phase trial comparing results with a previous study to find the best dosage and duration for future research.

How Is the Trial Designed?

Group I: Mifepristone 600 mg Experimental Treatment 2 Interventions

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.

Group II: Mifepristone 300 mg Experimental Treatment 2 Interventions

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.

Etanercept is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Enbrel for:

• Moderate to Severe Rheumatoid Arthritis
• Moderate to Severe Polyarticular Juvenile Rheumatoid Arthritis
• Psoriatic Arthritis
• Ankylosing Spondylitis
• Moderate to Severe Plaque Psoriasis

Approved in European Union as Enbrel for:

• Rheumatoid Arthritis
• Juvenile Idiopathic Arthritis
• Psoriatic Arthritis
• Ankylosing Spondylitis
• Plaque Psoriasis

Approved in Canada as Enbrel for:

• Rheumatoid Arthritis
• Juvenile Idiopathic Arthritis
• Psoriatic Arthritis
• Ankylosing Spondylitis
• Plaque Psoriasis

Who Is Running the Clinical Trial?

Nova Southeastern University

Lead Sponsor

Trials

103

Recruited

12,000+

RTI International

Collaborator

Trials

201

Recruited

942,000+

Miami VA Healthcare System

Collaborator

Trials

18

Recruited

2,400+

Published Research Related to This Trial

Etanercept has shown preliminary effectiveness in treating methotrexate-resistant polyarticular juvenile idiopathic arthritis (JIA), suggesting it could be a valuable option for patients who do not respond to standard treatments.

While most side effects of etanercept have been minor, two patients experienced a urticaria-like rash after injections, indicating that while generally safe, some individuals may have specific adverse reactions that need monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etanercept and urticaria in patients with juvenile idiopathic arthritis. Skyttä, E., Pohjankoski, H., Savolainen, A.[2017]

In a 24-week study involving 89 patients with rheumatoid arthritis who were not responding adequately to methotrexate alone, the addition of etanercept significantly improved clinical outcomes, with 71% of patients achieving a 20% improvement in disease activity compared to only 27% in the placebo group.

The combination therapy was safe and well tolerated, with only mild injection-site reactions reported, indicating that etanercept can be a beneficial addition to methotrexate for patients with persistent disease activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. Weinblatt, ME., Kremer, JM., Bankhurst, AD., et al.[2022]

Etanercept is a fusion protein that acts as a soluble receptor for tumor necrosis factor (TNF), effectively used to treat various chronic inflammatory diseases in humans, such as rheumatoid arthritis and psoriasis.

To study its effects in mouse models, researchers developed a murine version of the soluble p75-TNF receptor, allowing for better understanding of its mechanism in conditions that mimic human granulomatous infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Construction and purification of the murine p75-murine IgG1 fusion protein. Kim, HY., Renshaw-Gegg, LW., Balciunas, AM., et al.[2016]

Etanercept is an effective and safe treatment for rheumatoid arthritis (RA), significantly reducing disease activity and preventing joint damage, and can be used alone or with methotrexate for enhanced effectiveness.

While generally safe, etanercept requires caution due to potential risks such as re-activating tuberculosis and concerns about lymphoma, and it is recommended for patients who have not responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etanercept in arthritis. Scott, DL.[2015]

T0001, a new recombinant fusion protein, was found to be safe and well-tolerated in a first-in-human trial involving 56 healthy Chinese volunteers, with no serious adverse events reported.

The pharmacokinetics of T0001 showed a slow absorption and elimination rate, with increasing plasma concentrations of TNFα after administration, although the study could not confirm linear pharmacokinetics across the tested doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and immunogenicity of T0001, a newly developed anti-TNFα fusion protein, in healthy volunteers. Wang, Y., Liu, C., Chen, S., et al.[2018]

Preliminary reports suggest that etanercept does not increase morbidity or mortality in patients with HIV, indicating it may be a safe option for managing symptoms associated with HIV/AIDS.

Etanercept may help alleviate symptoms such as aphthous ulcers, cachexia, and fatigue in HIV/AIDS patients, while also managing related rheumatic diseases, but further research is needed to confirm its long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of etanercept in human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) patients. Ting, PT., Koo, JY.[2015]

In a study of 22 patients with severe and refractory psoriasis, 96% showed significant improvement in their disease severity after 12 weeks of treatment with etanercept, and this improvement was maintained until week 24.

Etanercept was well tolerated by patients, with no significant adverse reactions reported, although the average time until relapse was approximately 2.27 months, indicating a need for further long-term safety and efficacy studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Refractory psoriasis treatment with etanercept]. Mahiques Santos, L., Martínez-Menchón, T., Sánchez Carazo, JL., et al.[2019]

Murine p75-Fc, a soluble TNF receptor protein, effectively inhibits TNF-induced IL-6 production in mice, with complete inhibition observed at doses of 5 and 15 mg/kg.

At a lower dose of 1.5 mg/kg, murine p75-Fc still significantly reduced IL-6 production, indicating its potential as a therapeutic agent in managing inflammatory responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamic effects of the murine p75-Fc fusion protein in mice. Hu, YL., Kim, HY., Kohno, T., et al.[2016]

In a randomized, double-blind, placebo-controlled trial involving 234 patients with active rheumatoid arthritis, etanercept demonstrated significant improvements in disease activity over 6 months, with 59% of patients achieving a 20% improvement compared to only 11% in the placebo group.

Etanercept was well tolerated and showed a dose-dependent effect, with no dose-limiting toxic effects, confirming its safety and efficacy as a treatment for rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Moreland, LW., Schiff, MH., Baumgartner, SW., et al.[2022]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK565209/

Results - Gulf War Illness: A Systematic Review of ... - NCBI Summary of the effectiveness and strength of evidence from placebo-controlled trials of nutritional supplements for treating Gulf War Illness, by symptom domain ...

2. withpower.com withpower.com/trial/phase-1-8-2021-40f8b

Etanercept + Mifepristone for Gulf War Syndrome (E/M Trial) However, there is no specific data provided about its effectiveness for Gulf War Syndrome. The studies mention improvements in conditions like rheumatoid ...

3. biorxiv.org biorxiv.org/content/10.1101/2025.04.30.651399

Computational modeling-directed combination treatment ... Computational modeling-directed combination treatment with etanercept and mifepristone mitigates neuroinflammation in a mouse model of Gulf War ...

4. hsrd.research.va.gov hsrd.research.va.gov/publications/esp/gulf-war-illness-REPORT.pdf

Gulf War Illness: A Systematic Review of Therapeutic ... Mindfulness-based stress reduction improved pain, cognitive functioning, fatigue, depression, and posttraumatic stress disorder (PTSD), while.

5. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT04255498?term=%22nova+southeastern%22

NCT04255498 | Understanding GWI: Integrative Modeling An open-label Phase I study will be performed with Etanercept (once a week for 4 weeks) followed by mifepristone (once a day for 7 days), followed by a 10-week ...

6. go.drugbank.com go.drugbank.com/drugs/DB00005

Etanercept: Uses, Interactions, Mechanism of Action Etanercept is indicated for the treatment of moderately to severely active rheumatoid arthritis in adults and in chronic moderate to severe plaque psoriasis

7. hsrd.research.va.gov hsrd.research.va.gov/publications/esp/gulf-war-illness-APP.pdf

Gulf War Illness 3. Risk of bias due to missing outcome data: 3.1. Were data for this outcome available for all, or nearly all, participants randomized?

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04927338

NCT04927338 | Study of Bacopa in Gulf War Illness Patients This phase II, double masked, randomized, placebo-controlled, two-arm study will evaluate cognitive function as evidence of efficacy of the nutraceutical ...