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Seropositive Chronic Lyme Disease
and the seronegative Chronic Lyme Disease treatment studies. A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of the Safety and Efficacy of Ceftriaxone and Doxycycline in the Treatment of Seropositive Chronic Lyme Disease Principal Investigator: Mark S. Klempner, M.D. Co-Investigators: Arthur Weinstein, M.D., Linden Hu, M.D., Allen C. Steere, M.D., and Gary Wormser, M.D. Participating Centers: The New England Medical Center, Boston, MA, and the New York Medical College, Valhalla, NY. Description of the Study: Lyme disease (LD) is the most common tick-borne infection in the United States. It is caused by Borrelia burgdorferi, a spirochete, that is transmitted to humans and other animals by Ixodes ticks. The natural reservoir for this infectious agent is rodents; however, other types of mammals and some birds also may become infected. As with many infectious diseases, the clinical signs of LD are variable and unpredictable. Early manifestations include a rash (erythema migrans), general malaise, and flu-like symptoms. Chronic manifestations include arthritis, as well as cardiac and neurologic manifestations that have been reported to remit spontaneously and recur even after antibiotic therapy. Recently, the term Chronic Lyme Disease (CLD) has been used to describe a condition of chronic or intermittent symptoms related to LD. The cause of CLD is not known, but several possibilities have been suggested. The first is that it is a manifestation of a chronic active infection by B. burgdorferi that has escaped control or eradication by conventional antibiotic therapy. A second possibility is that CLD may be due to damage caused by the original infectious process, including the triggering of post-infectious immune phenomena, despite eradication of the spirochete. A third possibility is the presence of a co-infection with other microorganisms also transmitted by infected Ixodes ticks. Objectives: The objectives of this study are to determine whether: [a] intensive antibiotic treatment benefits seropositive patients with CLD; [b] evidence of persistent infection with B. burgdorferi can be found in patients with CLD; [c] evidence of co-infection with other microorganisms can be found in patients with CLD; [d] specific clinical or laboratory parameters improve in patients receiving antibiotic therapy in contrast to patients given placebo; and, [e] specific parameters are predictive of a beneficial response, should it be observed. Design of the Study: Since this is to be a double-blind study, neither the patients nor their doctors (study personnel) will know whether they are receiving antibiotic or placebo. Patients enrolled in the study will be randomized (in a 1:1 ratio) to receive either antibiotic or placebo, which will be administered both intravenously and orally. Separate randomization schedules will be generated for each of the two study centers by the NIAID or its designate. Thus, only the NIAID or its designate will know who is receiving antibiotic or placebo; this will not be revealed to the study personnel or patients until the study has been completed and the results are ready to be analyzed. The study population will include a defined cohort of patients with CLD, who are seropositive for Lyme disease (by the two-test CDC-Dearborn criteria) at the time of enrollment, and who meet the inclusion and exclusion criteria established for this study. The antibiotic regimen will be ceftriaxone, 2.0 grams per day, administered once daily by the intravenous route for 30 consecutive days, followed by doxycycline, 100 milligrams given every 12 hours, by the oral route for 60 consecutive days. Placebos identical in appearance to the intravenous and oral antibiotics will be administered by the same routes, and for the same duration of time, to patients randomized to the placebo group. Primary analysis of the efficacy of the antibiotic therapy to be tested in this study will be determined by improvement in the patient’s health-related quality of life, as measured by the SF-36 Health Survey; it includes eight multi-item scales that measure physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Three additional multi-item scales from the medical outcomes study (MOS) will be used to measure cognitive functioning, pain, and role functioning, but they will not be used for primary analysis of efficacy of antibiotic therapy. The SF-36 Health Survey (and additional MOS measures) will be administered to study participants four times: at baseline (prior to therapy), at one month (end of intravenous treatment), at three months (end of intravenous and oral treatment), and at six months. Also, at baseline and at defined intervals during the course of these studies, specimens will be collected to test for (a) an immune response to B. burgdorferi antigens in serum and cerebrospinal fluid (CSF); (b) B. burgdorferi DNA in CSF; (c) viable B. burgdorferi in CSF; (d) B. burgdorferi antigens in urine; and, serum antibodies specific for possible co-infecting agents, e.g., Babesia microti. Questions: Any questions concerning participation in this study should be addressed to either Dr. Mark Klempner or Dr. Linden Hu at 1-888-LYME CTR (1-888-596-3287).
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