Design paperThe Antibiotic Treatment Trial of Gulf War Veterans' Illnesses: issues, design, screening, and baseline characteristics
Introduction
In 1990 and 1991, the United States deployed approximately 700,000 troops to the Persian Gulf during the Gulf War. There were relatively few combat- and noncombat-related injuries and diseases during this conflict in comparison with previous military campaigns. Most veterans of this conflict who became ill and received care from the Departments of Veterans Affairs (VA) or Defense (DoD) had diagnosable and treatable conditions 1, 2, 3. However, the symptoms of approximately 15–20% of those with illnesses have not been explained, and this constellation of symptoms has been termed Gulf War Veterans' Illnesses (GWVI) 4, 5, 6. While the acronym GWVI will be used to describe this constellation of symptoms occurring in many veterans of the Gulf War, similar illnesses have been noted after nearly every major conflict [7]. More importantly, similar disorders of symptom aggregation, such as fibromyalgia, chronic fatigue syndrome (CFS), and multiple chemical sensitivity (MCS), occur at a high background rate in the general population 3, 8, 9, 10, 11, 12.
Although several explanations have been offered as to the cause of illnesses among Gulf War veterans, none of the putative etiologic agents or conditions is currently supported by conclusive empirical or scientific evidence. Research into causes has encountered numerous problems obtaining valid measurements of the many plausible exposures related to Gulf War service. One explanation that has received widespread attention from Gulf War veterans and their advocates is systemic Mycoplasma fermentans infection. Nicolson and colleagues have been active proponents of this hypothesis 13, 14, 15, and based on their preliminary data some clinicians have been using doxycycline to treat GWVI. While additional data justifying the Mycoplasma fermentans hypothesis might have been useful, such as controlled studies of mycoplasma infection in deployed and nondeployed veterans and phase II studies of the effects of antibiotics on patients' symptoms, these additional studies would have taken years to complete. Since it was almost 10 years since the Gulf War exposure and these patients were still ill, the VA decided to proceed with a study of antibiotic treatment for GWVI.
The VA Antibiotic Treatment of Gulf War Veterans' Illnesses Trial is a 30-month, prospective, randomized, double-blind, placebo-controlled clinical trial that started in May 1999 and ended in October 2001. Its purpose is to determine if antibiotic treatment (i.e., doxycycline) directed against Mycoplasma species improves symptoms in deployed Gulf War veterans with GWVI. Gulf War veterans with GWVI who met all entry criteria and gave informed consent were randomized to receive either 200 mg/day of doxycycline or placebo. All participants were treated for 12 months with an additional 6 months of follow-up to determine relapse rates. There were 491 Gulf War veterans entered into the study at 26 VA and two DoD medical centers.
Section snippets
Issues in designing an antibiotic trial of GWVI
There are many issues involved in conducting a study of chronic multisymptom illnesses such as GWVI. The study's planning committee was required to come to a resolution on each of these issues prior to submitting a proposal for scientific review.
The first major issue concerned the likelihood that GWVI was caused by a mycoplasma infection. At the time the study was being planned, there was a paucity of controlled research supporting or refuting the hypothesis that systemic Mycoplasma fermentans
Study objectives
The study has one primary and three secondary objectives.
Primary objective: To determine whether a 12-month course of doxycycline treatment in deployed Gulf War veterans presenting with symptoms of GWVI and testing Mycoplasma positive improves patients' functional status (measured by the PCS of the SF-36V) compared to placebo.
Secondary objective 1: To determine whether doxycycline treatment reduces symptoms of GWVI, including pain, fatigue, and neurocognitive symptoms.
Secondary objective 2: To
Screening results
The medical records of potential participants were screened for the presence of inclusion criteria and absence of exclusion criteria. Those patients who appeared to meet the entry criteria were interviewed by the site investigator or his/her designee to discuss the purpose of the study, the treatment regimen, the randomization procedures, the risks, inconveniences, and possible benefits of participation, and the rights of research subjects. Patients meeting all entry criteria, except for
Baseline characteristics
Table 2 gives the demographic characteristics for the study patients. Patients had a mean age of about 41 years, were mostly males (85.5%), white (63.5%), married (68.2%), with at least a high-school education (96.9%), and employed (77.6%).
The baseline PCS, MCS, and symptom scale scores of the patients are given in Table 3. The PCS and MCS scales are standardized scores based on population norms so that the population mean is 50 with an approximate standard deviation of 10. Lower scores
Discussion
The study of a multisymptom illness such as GWVI is not as difficult in its conduct as in its concept. The nonspecific nature of the illness, its etiologic uncertainty, and lack of an accepted overall outcome measure present significant design problems. While the hypothesis of a mycoplasma etiology raises issues such as choice of treatment, length of treatment, and how to determine Mycoplasma presence, this hypothesis offered some advantages. First, there is a clear and testable hypothesis
Acknowledgements
This study is supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development and Department of Defense. Study drug and placebo were donated by Pfizer Pharmaceuticals. The ideas expressed in this article are the private views of the authors and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences, Department of the Army, Department of Defense, or the U.S. Government.
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