Patients suffering with Gulf War Illness (GWI) are negatively impacted by a myriad of symptoms that vary among patients and include tiredness, headaches, stomach issues, and loss of memory and reasoning. These symptoms may be of sufficient severity and interfere with daily functioning and quality of life. Other symptoms include muscle pain, respiratory problems and skin conditions. Currently, treatment is focused on ameliorating symptoms, as the cause and persistence of this chronic condition is poorly understood, despite researchers gaining insight into some potential mechanisms of disease activity. Clinical and basic science studies have shown that disturbances in energy production and immune function play a key role in disease progression.

Therefore, the overall goal of the clinical trials outlined in this consortium is to target treatment more effectively to improve outcomes and quality of life for those suffering with GWI.

Over the last 4 years, both Dr. Klimas and her research team as well as Dr. Sullivan and her research team through their respective, previously funded GWI Consortia (GWIC) have identified markers of disease activity including but not limited to energy production, immune function and inflammation. In addition, both research teams understand that GWI is a complex disease state comprising of contributions from different systems within the body, which is why they aim to collaborate within this proposed consortium. Their research suggests that treatment will rely on combination approaches that have synergistic effects and/or single drugs with multiple mechanisms of action. In addition, due to the myriad of symptoms tied to GWI that vary among patients, treatments may be effective only for particular subsets of patients, which is why the clinical trials designed in this consortium focus on similar targets of disease activity from different, well thought-out and validated approaches.

The trials proposed are based on the combined insight gained from Dr. Klimas’s and Dr. Sullivan’s GWICs. Specifically, Study 1 (phase 1) is based on Dr. Klimas’s GWIC findings and will evaluate a combination approach that targets inflammation and endocrine dysfunction using etanercept, an anti-TNF agent, and mifepristone, a synthetic steroid with anti-progesterone and anti-glucocorticosteroid effects. Study 2 (phase 2) is based on the findings from Dr. Sullivan’s GWIC and Dr. Dikoma Shungu’s imaging work in myalgic encephalomyelitis; the phase 2 study evaluate the mechanisms of oxidative stress during N-acetyl cysteine (NAC) supplementation in Veterans with GWI. NAC promotes biosynthesis of glutathione and functions as a powerful antioxidant. Conceptually, we expect the 8-week NAC supplementation will lower the elevated oxidative stress and address the mitochondrial dysfunction tied to GWI. We also expect to see improvement in brain GSH utilizing MRS imaging in a subset of study participants as a sensitive index of oxidative stress changes in response to supplementation. This study involves five sites: NSU, Boston University, Michael E. DeBakey VA Medical Center (MEDVAMC; Houston, TX), VA New Jersey Health Care System War-Related Illness and Injury Study Centers (WRIISC) (VANJHCS WRIISC; East Orange, NJ), and VA Palo Alto Health Care System WRIISC (VAPAHCS WRIISC; Palo Alto, CA). Among these, enrollment will occur at four physical sites (MEDVAMC, Boston, VANJHCS WRIISC, and VAPAHCS WRIISC), and NSU will enroll into the virtual site. The participants from virtual site will undergo MRS imaging at Weill Cornell for substudy participants. Boston will also be a site where imaging will be performed. Lastly, Study 3 will evaluate a nutraceutical, Bacopa, with high therapeutic index, for its effect on cognitive function and biological response to 12 weeks of intervention. Bacopa has been shown to have antioxidant, immunomodulatory, and anti-inflammatory effects in addition to its ability to modulate dopaminergic and cholinergic neurotransmitter system. The Veterans with GWI can enroll in this completely decentralized double blinded randomized phase 2 study, which is under an Investigational New Drug from anywhere in the nation.

It is a key objective of this consortium to quickly deliver treatments to patients suffering from this debilitating illness. Based on our early experiences with combination synergistic approaches, as well as single drugs with multiple mechanisms of action, we truly believe that the targets in this proposal will help to improve energy production, restore immune function, and reduce inflammation. They will provide a more targeted approach to improve patient outcomes, halt disease progression, and reset dysfunction tied to the disease, at least in a subset, if not in all, patients with GWI.