The Use of B-Cell Depletion Therapy (BCDT) in Gulf War Illness: A Phase 1/2 Study

Principal Investigator/Project Director

Nancy Klimas

Colleges / Centers

Dr. Kiran C. Patel College of Osteopathic Medicine

Funder

DOD - U.S. Army Medical Research Acquisition Activity

Start Date

9-30-2017

Abstract

Background: GWI (also known as Gulf War Syndrome (GWS)) is a chronic multi-symptom illness that has been implicated in as many as one-third of the 700,000 U.S. troops deployed to the Middle East during the 1990-1991 Gulf War. The underlying mechanisms tied to GWI that result in the varied and debilitating symptoms are poorly understood, which has resulted in treatments that have been palliative at best. While investigators have evaluated the underlying mechanisms of disease and targeted treatments for two decades, researchers have fallen short of clearly understanding mechanistic pathways tied to disease and determining specific targets for treatment. However, more recently, there have been significant advances in gaining insight into potential mechanisms of action through strong epidemiologic, clinical, and basic science studies. These studies have carved out potential biomarkers that maybe tied to disease severity and/or serve as targets for treatment. Specifically, immune inflammatory biomarkers, which have been implicated in GWI, can be used as biomarkers to identify targeted therapeutic interventions or biologic response modifiers. In this application, we aim to target two different immune pathways, the pro-inflammatory cytokine cascade as well as interfering with autoantibody production. By inhibiting autoantibody production using a b-cell depleting therapy, we not only hope to decrease the presence of autoantibodies but decrease pro-inflammatory cytokine expression and reset underlying mechanisms of disease by wiping out B-cell memory cells to prevent future autoantibody production. Objective/Hypothesis: Our objective is to engage a team of highly qualified researchers to evaluate the efficacy and safety of rituximab, validate the presence of CNS autoantibodies and decrease their presence with b-cell depleting therapy such as rituximab and reset underlying mechanisms of disease to improve symptoms and reset homeostasis. Specific Aims: (1) To evaluate the safety of rituximab, relative to placebo in GWI. (2) To evaluate the effect of rituximab, relative to placebo, on changes in Short Form-36 (SF-36) combined physical health summary and vitality subscale scores and overall response relative to baseline during 9 month follow up. Overall response is defined as mean improvement in SF-36 score of at least 4.5 for at least 4 consecutive weeks for moderate response and at least 5.0 for at least 4 consecutive weeks for major response. (3) To determine the levels of autoantibodies against neuronal glial proteins as follows immediately before administering rituximab and 6 weeks, 3 months, 6 months and 9 months after initial administration of rituximab or placebo. This will allow an initial evaluation of the clinical condition and symptom complex of veterans with GWI and the levels of autoantibodies and changes in antibody level against neural proteins. Study Design: Phase I/II trial randomized, double-blind, placebo controlled single-site study. This study will compare treatment with rituximab or saline solution; two infusions with two weeks’ interval (500 mg/m2, max. 1000 mg), followed by nine months of observation and assessment. The double-blind design will be maintained until the last included patient has been assessed at 9 months of follow-up. Clinical Impact: If proved effective, the results could change the standard of care for GWI illness, targeting the underlying cause of disease and not just ameliorating symptoms. The use of a b-cell depleting therapy such as rituximab not only may prove that blocking autoantibodies force a homeostatic shift but also prove that the autoantibodies seen in GWI are indeed mediators of illness persistence. In this complicated disease with minimal treatment approaches that only target symptomatology, this study poses to provide an understanding of disease onset and progression and provide a targeted therapy for at least a sub-group of patients with GWI and drastically change the dynamic of treatment. This not only sets to determine an underlying cause of disease but change the course of treatment by moving from amelioration of symptoms to resetting homeostasis.

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