TNF and Glucocorticoid Antagonist for GWI Associated Multi-symptom Disease Homeostasis Reset

NCT04254627 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: GWICTIC-EMphase1CDMRP-PC16GW170044
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

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.

Conditions

Gulf War Illness

Keywords

Gulf War Illness; Veterans; etanercept; mifepristone; VA Healthcare; TNF; Multi-symptom disease; Phase I

Outcome Measures

Primary Outcomes (2)

• Safety - incidence and severity of adverse events

  Safety is assessed by the incidence and severity of adverse events, by relation to the study intervention.

  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.

  Baseline and 24 weeks

Secondary Outcomes (1)

• Homeostatic network correction

  Baseline and 24 weeks

Study Arms (2)

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.

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.

Drug: Etanercept; Drug: Mifepristone

Interventions

Etanercept DRUG

Etanercept 50 mg weekly injection

Also known as: Enbrel

Mifepristone 300 mg; Mifepristone 600 mg

Mifepristone DRUG

Mifepristone 300 mg pill

Also known as: Mifeprex, RU-486

Mifepristone 300 mg; Mifepristone 600 mg

Eligibility Criteria

• Age: 45 Years - 70 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years old,
• Male sex,
• In good health by medical history prior to 1990
• 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.
• 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.

You may not qualify if:

• 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
• 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.
• 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.

Sponsors & Collaborators

• Nova Southeastern University: lead
• RTI International: collaborator
• Miami VA Healthcare System: collaborator

Study Sites (2)

Nova Southeastern University

Davie, Florida, 33314, United States

Location

Miami VA Healthcare System

Miami, Florida, 33125, United States

Location

MeSH Terms

Interventions

Etanercept; Mifepristone

Intervention Hierarchy (Ancestors)

Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Nancy Klimas, MD

  Miami VA Healthcare System

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2020
• First Posted: February 5, 2020
• Study Start: September 24, 2021
• Primary Completion: September 1, 2025
• Study Completion: September 1, 2025
• Last Updated: February 19, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)