National Institute of Allergy and Infectious Disease (NIAID)
12 June 2001
Results of the first randomized, placebo-controlled, double-blind trials testing antibiotics in patients with a stubborn form of Lyme disease those whose symptoms persist after standard courses of antibiotics validate that these patients suffer significant pain and other disabling symptoms. The two trials found, however, that a 90-day course of intravenous and oral antibiotics was no better than placebo at improving these chronic symptoms.
Because of their potential importance to Lyme disease treatment, The New England Journal of Medicine is publishing these findings today online at http://www.nejm.org. The report will appear in the July 12th print edition of the journal. The studies were funded by a National Institute of Allergy and Infectious Diseases (NIAID) contract to Mark S. Klempner, M.D., of Boston University School of Medicine.
"Our results suggest that we need to define the cause or causes of the debilitating, persisting symptoms experienced by some patients with Lyme disease. Understanding the origin of these symptoms should lead to more effective therapeutic approaches to ameliorate these symptoms," says Dr. Klempner. "Based on experience with other chronic infectious diseases caused by persisting bacteria syphilis, tuberculosis, and ulcers, for example we think it is unlikely that a longer course of treatment or different antibiotic combination would result in greater improvement than what we found in these studies."
Significantly, more than 700 different blood and cerebrospinal fluid samples were collected from the study volunteers. None of the samples showed evidence of persistent infection with the Lyme agent, Borrelia burgdorferi. This suggests, Dr. Klempner says, that researchers should investigate autoimmune and other processes to determine whether they play a role in a least some of the symptoms of chronic Lyme disease. The trials were carried out by primary investigators and their staffs at three centers: New England Medical Center in Boston (Dr. Klempner's former affiliation); New York Medical College in Valhalla (Arthur Weinstein, M.D.); and Yale-New Haven Hospital in Connecticut (Janine Evans, M.D.) Volunteers were recruited through hundreds of screening clinics set up in schools, hospitals, and town halls located in these areas where Lyme disease is highly endemic.
A total of 129 volunteers enrolled in the two studies. All participants had well-documented Lyme disease and had previously received at least one course of recommended antibiotics. Despite prior antibiotic treatment, the volunteers currently suffered from persisting muscle or joint pains and complained of memory and thinking problems, often associated with fatigue.
Although both trials were identical in design, one trial enrolled 78 chronic Lyme disease patients who tested positive for antibodies to the Lyme bacterium, while the other trial enrolled 51 people with chronic symptoms but no evidence of antibodies.
In each study, volunteers were assigned at random to receive either antibiotic treatment or an inactive placebo. Treatment consisted of intravenous ceftriaxone, 2 grams daily, for 30 days, followed by oral doxycycline, 200 milligrams daily, for 60 days. The investigators evaluated symptom improvement based on the patients' responses to a health-related quality-of-life questionnaire given 90 days after they completed the course of antibiotic treatment or placebo.
An interim data analysis planned into the design of the trials was carried out last November by a Data and Safety Monitoring Board (DSMB), an independent group of doctors and researchers. The DSMB unanimously recommended that NIAID stop the treatment arm of both trials because the data showed no significant difference in the percentage of patients who received either antibiotic treatment or placebo who felt their symptoms had improved, worsened, or stayed the same: a little more than one-third felt better, about one-third felt worse, and slightly less than one-third felt the same. The DSMB's review suggested that even with continued accrual of another 131 patients, the number needed to reach full enrollment, there was only a slight chance a difference between the antibiotic treatment and placebo groups would be found. NIAID agreed with the DSMB's recommendation, as well as their recommendation that the investigators continue to follow the patients to monitor them for safety and to learn more about possible causes of chronic Lyme disease.
"Although we still have much to learn," says Dr. Klempner, "we know much more about chronic Lyme disease now than we did when these studies began." Besides the information obtained about the efficacy of intensive antibiotic treatment, the investigators found that the impact of Lyme disease on physical health was at least equal to the disability of patients with congestive heart failure and osteoarthritis. Some patients were also found to have cognitive impairment.
"The antibiotic treatment component is only one piece of NIAID's comprehensive clinical studies on chronic Lyme disease," adds Phillip J. Baker, Ph.D., who oversees NIAID's Lyme disease program. "These studies have yielded a considerable amount of new information. We intend to characterize the patients enrolled in the study as thoroughly as possible to learn more about the mechanisms involved in chronic Lyme disease," Dr. Baker adds. "The knowledge obtained from such studies should be of immense value in developing new, more promising approaches for treating this disease."
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
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The National Institute of Allergy and Infectious Diseases is a component of the National Institutes of Health, U.S. Department of Health and Human Services.
MS Klempner et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. New England Journal of Medicine vol. 345(2), July 12, 2001.