Some Interesting Materials on the NIH Study

This is an excerpt of some very complete materials found at: http://www.geocities.com/HotSprings..dy-complete.txt Greg I think that you might comment on this. I found the part about an "overall climate that discouraged questioning" to be revealing, and to provide a counterpoint to your insistence that there was a failure of "collective" vision, and your points that the patient community didn't speak out. This writer certainly hits the nail on the head. So what was with Phyllis and Carl? I'm going to provide some more items of interest on this thread. Perhaps it will spark some debate about the relevant issues? ----------------------------------------------------------------- Subject: Open Letter re: NIH LNB Study and Int'l Congress Date: 01 Jul 1996 00:00:00 GMT From: kramer@listen.com (Gregory Kramer) Organization: Clarity/Santa Fe Institute Newsgroups: sci.med.diseases.lyme June 24, l996 RE: VII International Congress on Lyme Borreliosis June 16-21, l996 The Fairmount Hotel San Francisco, California An Open Letter to the Chronic Lyme Disease Patient Population I have just returned from San Francisco and feel an obligation to report to the chronic Lyme disease patient population what I learned at the VII International Congress on Lyme Borreliosis. NIH is about to award its first contract for clinical trials and it is important that the Lyme patient community have a clear understanding of the climate in the research community. Background For many years the patient population suffering from what may be refractory disease has been lobbying for research into chronic neurological Lyme disease. An overview shows that in February of l993 the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Allergy and Infectious Disease (NIAID) invited research grant applications seeking support of a wide spectrum of research directed at generating improved knowledge concerning Lyme disease of the nervous system." (1) Research objectives stated in this PA were that "neurological involvement is a frequent clinical manifestation of Lyme disease. In addition, it has been suggested that the CNS may serve as a reservoir for persistent infection. Central issues about neurological aspects of Lyme disease are unresolved, including the definition of neurological disease in adults and children in the choice and duration of therapy. The pathogenetic mechanisms which produce central and peripheral nervous system syndromes are unknown; in particular, the etiology of persistent post-infectious symptoms and their optimal management is unclear." (2) The PA went on to say: "Examples of research goals, many of which could be studied in humans as well as animal models and tissue cultures and are appropriate for pursuing an application in response to this PA, include, but are not limited to: - The epidemiology of the neurological aspects of Lyme disease, especially in endemic areas. Identification of neurological syndromes in children and adults that can be reliably attributed to this disorder, including both primary and post-infectious syndromes. - Studies of diagnostic laboratory abnormalities which correlate with the various syndromes, including cerebrospinal fluid, serum, neurophysiological, and neuroimaging testing. - Studies of mechanisms of pathogenesis in development of encephalopathy, encephalomyelitis, and neuropathies. - Characterization of the severity and frequency of cognitive impairments in LNB, and studies of correlated laboratory parameters, and their response to therapy. - Studies of immune-mediated and other pathogenic mechanisms role in injury to the nervous system. This may involve spirochete interactions with the immune system, and definition of immune and inflammatory abnormalities, including studies of auto- antibodies, cytokines, cellular immune responses, and immune complexes. - Development of effective drug regimen(s). Optimization of antibiotics, drug dosage, and treatment duration. Development of therapeutic approaches for patients who have persistent neurological symptoms. This could be accomplished by controlled clinical trials. - Studies of the molecular basis for B. burgdorferi neurotropism and the role of strain differences in pathogenesis. - Development of reliable animal models for studies of nervous system infection and studies of viral latency neuropathogenicity." (3) Recently, in April of this year at the IX Annual International Conference on Lyme Borreliosis & Other Tick-Borne Disorders and then again at the VII International Congress just held in San Francisco, Dr. Adriana Marques , Principal Investigator announced "A New NIH Intramural-Extramural Collaborative Study of Chronic Neuroborreliosis." This study's introduction stated "..the full range of disorders associated with Lyme disease is not certain, and there are particular problems in diagnosing individuals without classical symptoms. The lack of definitive diagnostic technique for certain forms of Lyme disease has hampered our ability to answer important questions, particularly regarding persistent forms of the disease. We need objective markers of infection, of clinical status and of host responses to the organism to discern the scope and implications of persistent borrelial infection; as well as to assess the effectiveness of current and new treatment options. One fundamental question that we face is whether persistent signs and symptoms of disease, especially neurologic ones, are due to ongoing active borrelial infection or due to other pathogenic mechanisms." (4) Extramural Clinical Trials There were two extramural proposals submitted for inclusion in the NIH Intramural-Extramural Collaborative Study for clinical trials of chronic LNB. The content of neither proposal has been released and the Review Committee has not been and I gather is not traditionally disclosed. What I report to you here is what I learned in numerous conversations with many individuals over the five day conference period. I have tried to include only information which I feel is fairly reliable. Although the awarding of an extramural contract for clinical trials was not announced at the VII International Congress , it is common knowledge in the community that the grant will be going to the New England Medical Center, Boston, MA with Mark Klempner as Principal Investigator. Additional investigators on the contract to the best of my knowledge include Alan Steere, Eric Logigian, Gary Wormser, Jesse Goodman, and others. The only other proposal submitted was from the State university of NY at Stony Brook with Benjamin Luft as P.I. ,and Patricia Coyle, Raymond Dattwyler, Robert Schoen, Thomas Rush, and others. Conference attendees believe that Alan Barbour and Andrew Pachner were members of the Review Committee. Proposals were submitted by the two institutions for clinical trials in the chronic neuroborreliosis patient population. There was discussion among conference attendees that it was believed that New England Medical Center (NEMC) was given an advantage in that they were extended an opportunity to revise their initial grant proposal with guidance from NIH and that this opportunity was not extended to Stony Brook. As mentioned, I am not clear as to the content of the proposals but I do understand that both proposals asked for clinical trials of 4 weeks IV antibiotics. There was inclusion of oral antibiotics in the Stony Brook (SUNY) study and I am not sure whether or not they were originally included in the New England Medical Center Study. Discussions were ongoing with NEMC regarding oral antibiotics and (whether or not they would be included at all in the NEMC study and (if they were included would they be concurrent with or subsequent to the parenteral antibiotics. Patients in both studies were to be followed and evaluated at end point of treatment, three, six and twelve months post treatment. Patients who did not remain off antibiotics and palliative treatment for the full year would be dropped from the study. I have no idea how the attrition population would be interpreted. Both studies were double-blinded and included placebos. VII International Congress on Lyme Borreliosis The International Congress in San Francisco provided a revealing look at the status of the dynamics of the Lyme research community. The following are perhaps instances that are indicative of the on- going climate: **The first Plenary Session of the Congress was on Epidemiology and Surveillance. It was moderated by Dr. Alan Steere and included presentations by David Dennis of the CDC and Johan Berglund from Sweden. At the conclusion of the presentations a number of conference attendees rose to ask questions. The first question was from Dr. Daniel Cameron of Mt. Kisco, NY. Dr. Cameron asked a question and received a reply and was about to either ask another question or comment when Dr. Steere interrupted brusquely with the statement "we are not going to do this", dismissed Dr. Cameron and took the next question. Many attendees, including European researchers unaware of the two sidedness in the American Lyme community, were fairly horrified with the tone of this dismissal. **Patricia Coyle in a presentation on June 18 on "Cerebrospinal Fluid Findings in Neurologic Lyme Disease" presented her data on specific and non-specific CSF findings and stated very emphatically that she believed that chronic Lyme disease was primarily a neurological illness. In the presentation she said ".. a certain percentage may have chronic active infection.. I believe a persistent CNS infection is a possibility." Two days later, in another session after a presentation entitled "Detection of Borrelia burgdorferi DNA by Using an Osp-A Based PCR in Cerebrospinal Fluid from Patients with Lyme Neuroborreliosis and Direct Genotyping of the Obtained Amplicans", Dr. Duane Gubler of the CDC, one of the two conference hosts, asked a question of the European presenter. Gubler said that he was very confused because the European data was very much in direct contrast to Dr. Coyle's previously reported data. He asked are we really being asked to believe that we are dealing with such different genospecies of spirochetes in the US that we would be getting such contrasting results in the CSF. The response he received from one of the session's moderators, whom I believe was Dr. Hansen (co-author of the paper just presented), was that he felt that Dr. Coyle was using the wrong test and allegedly looking at the wrong patients. Drs. Steere and Pershing quickly lined up to agree that their data replicated the European data just presented. Dr. Coyle asked for and was granted five minutes to respond the next day. It was not missed by conference attendees that Dr. Gubler rose and excused himself from the room as lights were being dimmed for slides. Scientific data aside many conference attendees viewed this as a backhanded rebuff of Dr. Coyle. It might be reasonable to think that professional courtesy would have indicated that questions regarding Dr. Coyle's data and interpretation would have been addressed to Dr. Coyle directly. This should not be misconstrued as support for Dr. Coyle but simply as an illustration of what happens to a researcher who reports data that does not fit the dominant Lyme model. It also may indicate a rigidity on the part of researchers and administrators who believe that all the answers are in. **Many attendees from the patient community and a segment of the professional researchers continue to feel that there is an on-going "sanitization" of Lyme disease. This takes the form of more restrictive diagnostic criteria; the view that the disease is over diagnosed; that the problem is not Lyme disease but Lyme paranoia; and the fallback position that "the most common reason for symptoms after standard courses of antibiotics in patients with suspected Lyme disease is misdiagnosis." *Dr. David Dennis of the CDC decried the quantity and cost of Lyme disease testing in the US. *Dr. Robert Kalish of Tufts university School of Medicine, New England Medical Center presented a "Ten- to Twenty Year Follow-up of Study Patients with Lyme Disease in the Lyme, Connecticut Area." In this study, a computerized random sample of patients was evaluated for long term morbidity. In his oral presentation, Dr. Kalish indicated that they removed from the study patients who had returned to Dr. Alan Steere over the years for chronic problems. Dr. Kalish was asked later during his poster presentation if the chronic patients removed from the study had more significant neurocognitive differences than those who remained in the study. He said yes but they removed the chronic patients from the study because they already knew they were having problems (!). *Elyse Seltzer in her presentation on the "Long-Term Outcomes of Persons with Lyme Disease" concluded that the prognosis for most Lyme disease patients is excellent and there was no significant functional impairment in the Lyme disease patients they assessed in CT. *One of the investigators who would be part of the New England Medical Center Study indicated that they (NEMC) do indeed view neuroborreliosis as active infection but after three months of treatment they definitely would not attribute ongoing symptomology to active infection. While the entire Congress was not devoid of occasional references (mostly in poster sessions) of rare cases in need of re-treatment or an occasional mention of treatment failure, the chronic disease seems to garner little attention. Rocky Mountain Labs, however, continues to present compelling and important research. Dave Dorward presented his data, including slides, of spirochetes "coating" themselves in human material in his presentation "Invasion and Killing of Human B- and T-cells by Borrelia burgdorferi." Alan Steere did inquire at the end of the presentation whether Dave Dorward believed this "coating" phenomenon could last for weeks or even months. Dave Dorward said he believed that it was possible and indeed they have even viewed coated spirochetes re-coating themselves. Discussion Given an overall climate at the VII International Congress that seems to discourage questioning, combined with what appears to be an undisputed acceptance of a paradigm that all but denies the possibility of chronic LNB that is unresponsive to antibiotics, we need to take a look at the proposed clinical study. Failure of four weeks of IV antibiotics (or eight or twelve or more for that matter) with or without oral antibiotics is how the chronic patient population became chronic. Many chronically ill Lyme patients are not chronic for lack of treatment. There are indications that they are chronically, and in many cases progressively ill because of continued infection by an agent that is minimally responsive to antibiotic treatment. Chronically ill patients use antibiotics for control, not bacteriological cure. There are too many people, researchers and patients alike, stuck in the belief that the disease is currently curable. We need research that will move us beyond antibiotics as cure. This is a difficult jump to make. Patients must face living with the disease while researchers and clinicians must admit the frustrations associated with the current state of scientific knowledge. In some cases researchers may need to simply admit they were wrong. Only then can we seriously begin to engage in a research program that will hold promise for substantial mitigation of symptoms or a cure. Based upon the anecdotal but very broadly available data in the chronically ill population, it is evident that at the end of this study questions will still remain regarding persistent infection. If the study looks at the correct patient population, some patients will improve and then relapse but more likely many will not remain in the study because of the inability to maintain a functional existence off antibiotics; and, the technology simply does not exist to rule out active infection. At the close of this study, questions regarding persistent infection will remain but belief in the efficacy of antibiotics will be significantly compromised. There exists great pressure to develop treatment protocols that would include choice of antibiotic, drug dosage and treatment duration. Any study that questions the efficacy of antibiotics will, in the hands of the insurance companies. deal a devastating blow to patients seeking treatment approval. The price of treatment denial is immeasurable in loss of patient functionality and progression of the disease. And since the questions being asked assume a binary "antibiotics are/are not effective" outcome, the knowledge base relevent to other solutions, e.g. antibiotic delivery mechanisms, will not be further advanced. The awarding of the contract to NEMC should be of deep concern to us. It is very appropriate for us to ask how there will be a fair interpretation of the data when so many of the investigators, both individually and jointly, have a long term published bias to the concept of active infection. It is true that Mark Klempner and not Alan Steere will be the P.I., and that Dr. Klempner has presented data pointing to intracellular location of spirochetes. However, these facts offer little comfort in light of the fact that Tufts and NEMC have driven the "overdiagnosed and easily treated" and "post-Lyme syndrome" machinery that has done so much damage to the patient seeking diagnosis and treatment (let alone re-treatment). Conclusion Five million dollars has been allocated for research on chronic neuroborreliosis. The contract for the extramural LNB study is about to be awarded. The cummulative chronic patient experience evidences siginifcant numbers of treatment failures with antibiotic treatment . The NIH has raised "one fundamental question ..whether persistent signs and symptoms of disease, especially neurologic ones, are due to ongoing active borrelioal infection or due to other pathogenic mechanisms." (5) The research history of the institutions being funded as well as the beliefs of at least one alleged member of the Review Committee indicate misdiagnosis as the primary reason for treatment failure. And the patient community, in the midst of a tightening trend amongst health care providers and insurance companies, finds itself in the middle of a study that will look at the efficacy of antibiotics not the mechanisms of on-going disease. And as if that isn't bad enough, we may wind up with research that will lead to reinforcement of a faulty paradigm that will negatively impact future research directions. As stakeholders in this research program we need to examine these issues individually and collectively . We need to discusss these concerns with our families, friends, physicians, support groups, legislators and NIH. It was indicated at the VII International Congress that the particulars of the study have not been completely resolved. There is room for patient input and now is the time to make your feelings known. We are going to have to live with the results of this research for a very long time. July 1, l996: It is my understanding the the awarding of the research study to the New England Medical Center has now been publicly announced. Footnotes: (1) NIH, Neorological Aspects of Lyme Disease, Volume 22, Number 5, February 5, (2) l993. (3) Ibid. (4) Ibid. (5) A New NIH Intramural-Extramural Collaborative Study of Chronic Neuroborreliosis, NIH. (6) Ibid. sci.med.diseases.lyme: Open Letter re: NIH LNB Study and Int'l Congress http://groups.google.com/groups?num..48.teleport.com

PART 1 http://www.geocities.com/HotSprings..dy-complete.txt NIH chronic Lyme disease study information on internet - complete file ************************************************************************ as of 22 June 1999 Basic information on the NIH chronic Lyme disease study: NIAID's Chronic Lyme Disease Study Questions and Answers In 1996, the National Institute of Allergy and Infectious Diseases (NIAID) awarded a five-year contract to the New England Medical Center (NEMC) to study how chronic Lyme disease develops and how to improve its treatment. This document answers general questions about these studies. It is important to keep in mind that this is a research project, designed to help scientists better understand Lyme disease, and to improve ways of diagnosing and treating this disease. Anyone with more specific questions not addressed in this document is encouraged to call the NEMC Lyme Disease Center at 1-888-596-3287. Q1: Why is NIAID funding this study? Although scientists have identified Borrelia burgdorferi as the bacterium that causes Lyme disease, we need to know much more about how it causes disease. Many questions remain about the chronic manifestations of Lyme disease. The question is not whether such a syndrome exists; rather, it is how B. burgdorferi elicits so many different long-term problems in some people. Currently, it is not known whether the symptoms associated with chronic Lyme disease are caused by one or more of the following: 1) an ongoing (persistent) infection with B. burgdorferi or other tick-borne pathogen; 2) reinfection with B. burgdorferi; 3) an autoimmune or inflammatory response associated with the initial infection; or 4) some other mechanism. Although the symptoms associated with chronic Lyme disease may result from persistent infection with B. burgdorferi, direct evidence of persistent infection usually is not found. Consequently, it is difficult for physicians to decide which treatment strategies are most effective. For example: * What types of antibiotics should be used? * How long should they be taken? * If beneficial effects occur, how long do they last? * Should drugs other than antibiotics be tested? * What outcomes can be used to determine that a given course of antibiotic treatment is indeed effective? This project is examining many of these questions in a stepwise and systematic manner. The research involves conducting a variety of laboratory tests, many not used before in patients with chronic Lyme disease, to characterize the disease in detail. The study also will determine the antibiotic approaches and monitoring techniques likely to prove most useful to doctors treating people with chronic Lyme disease. Q2: Who are the study researchers? Dr. Mark Klempner of the New England Medical Center heads the project. Dr. Klempner, together with the NIAID project officer, Dr. Phillip Baker, are responsible for the overall design and conduct of the studies performed under the contract. Dr. Arthur Weinstein coordinates all aspects of the study at Westchester County Medical Center/New York Medical College. Dr. Gary Wormser, also at New York Medical College, oversees the administration of study medications. In this role, he works closely with the nursing staff to minimize any adverse reactions to antibiotics and to reduce the risk of bacterial infections sometimes associated with prolonged intravenous therapy. He also cultures spinal fluid samples to look for the presence of viable B. burgdorferi. Dr. Jesse Goodman, university of Minnesota School of Medicine, conducts all laboratory tests to detect possible co-infecting agents (ehrlichia and babesia). Dr. Allen Steere of Tufts university oversees the serologic tests on patient blood samples. All these investigators are experts in their fields. Q3: How were the contract proposals reviewed and evaluated? A panel of non-NIH scientists reviewed and evaluated the contract proposals, ranking them according to scientific merit, the chief criterion considered in awarding a contract. The projected cost of carrying out the required work was another important factor considered. A contract proposal must provide evidence that the investigators can meet the scientific objectives established by the Institute. Thus, the review panel evaluated both the scientific expertise and the soundness of the experimental design of the applications. A sample protocol primarily enables the scientific reviewers to assess the scientific capability and research approach of the applicants. NIAID staff work closely with contract investigators at every step to refine the design of the treatment protocol so the studies achieve the defined objectives. Q4: Are clinical trials part of this research project? Yes, Phase III clinical studies to determine the effectiveness of a treatment are a major component of this project. These multicenter studies are being conducted in collaboration with scientists in NIAID's intramural research program in Bethesda and with other scientists elsewhere. The goal is to further characterize chronic Lyme disease so that rational, more effective therapies can be devised. These studies are double-blinded and placebo-controlled. That means all specimens to be tested are coded so that neither the investigators nor the patients know who is getting antibiotic and who is receiving placebo. Only after the study has been completed and all specimens have been analyzed will the codes be broken so the effectiveness of treatment can be evaluated. Such an approach ensures objectivity and rules out any possible bias or preconceived ideas about any aspect of the studies. Biostatisticians review the study protocols to determine how many patients must be enrolled to obtain conclusive, statistically meaningful results. Q5: Who is overseeing the research? Dr. Phillip Baker, the NIAID project officer, has final approval of all studies that are undertaken. As with all Phase III clinical studies, an independent Data and Safety Monitoring Board (DSMB) -- appointed by the National Institutes of Health (NIH) -- regularly evaluates the results obtained. In addition, NIAID has established an advisory body made up of research scientists, medical experts and members of Lyme disease patient advocacy groups to help define the issues to be addressed and to resolve any problems that may arise during the course of these studies. Q6: How do the NEMC studies relate to the NIAID clinical trial conducted at the NIH? NEMC researchers work closely with NIAID intramural investigators, although the criteria for selecting patients for each study are different. In the NEMC studies, patients must have had a documented case of acute Lyme disease, have received treatment and recovered, but subsequently have developed all the signs and symptoms associated with chronic Lyme disease. In contrast, patients enrolled in the intramural studies are more likely to be actively infected based on the results of a variety of laboratory tests. Additionally, the NEMC studies have a placebo arm, whereas all patients in the intramural studies receive an antibiotic. The intramural study patients receive antibiotics because they are most likely to be actively infected, and therefore it would be unethical to give any of them a placebo. Together, the investigators in the two studies will determine if the immunologic and diagnostic tests used to monitor the effectiveness of antibiotic therapy prove useful for some or all of the patients in the study. The studies are employing experimental tests not currently available to physicians, and NIAID staff hope that these tests will provide valuable insights into chronic Lyme disease and help doctors evaluate the effectiveness of antibiotic treatment. Q7: People in the intramural studies must have a positive Lyme antibody test and Western blot. Do the NEMC studies also require such tests, even though some people with symptoms of chronic Lyme disease are seronegative? These antibody tests are used in the initial diagnosis of early or acute Lyme disease, the major population selected for enrollment in the intramural studies. Although the patients in the intramural studies must have positive ELISA and Western blot tests, indicating the presence of B. burgdorferi antibodies, patients in the NEMC studies, who have chronic Lyme disease, are divided into two groups (seropositive and seronegative), and thus do not have to be antibody-positive at the time of enrollment. However, they must be able to document that they have been diagnosed with Lyme disease in the past. Q8: Previously I had a positive Western blot test for Lyme disease. Why am I required to currently test positive by Western blot to enroll in the seropositive group? Because the reliability and reproducibility of blood tests for Lyme disease are somewhat controversial, requiring a current positive Western blot ensures that all the patients in the study will have a standardized blood test done under the same conditions and within the same timeframe. If screening tests indicate that a volunteer is seropositive, he or she can be admitted to the seropositive group or arm of the study. Seronegative patients can participate in the study, too; however, they are enrolled in the seronegative group. Both groups receive the same treatment. Q9: Why are patients who test positive by polymerase chain reaction (PCR) for B. burgdorferi at the time of initial evaluation being excluded from the study? After enrollment, patients are selected at random for assignment to either the placebo or antibiotic treatment group. Patients who test positive for B. burgdorferi by PCR are considered to be actively infected. Thus, these patients are excluded from the NEMC placebo-controlled study to avoid the possibility that they will be selected at random to receive placebo instead of treatment. Such patients are referred to the NIAID intramural study on Lyme disease, which has no placebo group; there, all patients are treated with an antibiotic since multiple tests (including PCR) indicate that they are probably actively infected. Q10: The enrollment criteria state, "Persons who have serious pre-existing or concurrent chronic medical or psychiatric illnesses are excluded from the study." What types of psychiatric illnesses does this include? If I have been diagnosed with depression, would that exclude me from the study? Questions like this can best be handled on a case-by-case basis and should be referred to the investigators of the study. Our goal is to enroll a group of patients in whom the therapy used can be evaluated unequivocally. This would be difficult, if not impossible, to do if patients have more than one diagnosis that could account for some of their symptoms. Q11: Why is there a placebo group in the study? Patients given placebo often appear to improve by as much as 30 to 40 percent. Although the basis for this "placebo effect" is not known, it is important to include a placebo group to ensure that the beneficial effects of any treatment under study are significantly greater than what can be attributed to the placebo effect alone. Patients are not given placebo if there is direct evidence of active infection or if there is reason to believe that their condition would worsen if they are not treated. Q12: The Lyme Urine Antigen Test (LUAT) has been included in the study. Does that mean that the test is generally seen as valid? The NIAID Lyme Disease Advisory Panel requested that the LUAT be included in the study to gather information on the test's utility. Its inclusion in the study does not imply endorsement of LUAT, which has not been approved by the FDA as a valid diagnostic test for Lyme disease. Rather, an important aspect of the study is evaluating the utility of both new and old tests in the diagnosis and management of patients with Lyme disease. Q13: Why must patients enrolled in the study have a lumbar puncture (spinal tap)? Because the symptoms associated with chronic Lyme disease are mainly neurologic, there is reason to believe it may result from a persistent infection of the nervous system. Therefore, laboratory tests performed on samples of cerebrospinal fluid (CSF), which are obtained by lumbar puncture, provide a means to look for abnormalities that can be associated with central nervous system disorders. Q14: Why does the study have only a single treatment option? Why not include intravenous treatment at differing time intervals =96 say 4, 6 and 8 weeks? The inclusion of multiple time intervals or different antibiotics, for that matter, would require substantially more patients to be enrolled in the study, and would exceed the allotted study budget. Should the 12 week treatment being evaluated be found to be beneficial, future studies can be designed to test the effectiveness of shorter intervals using either the same or different combinations of antibiotics. Q15: Are patients reimbursed for travel expenses to reach the study sites? Our goal is to facilitate easy transportation to and from the study sites. Free parking is provided, and through a close working relationship with several travel agencies, access to study sites is made as easy as possible. More specific questions concerning reimbursement for expenses should be addressed to the principal investigators associated with the studies. Q16: Who will have access to my medical records and the name of my physician? All medical records will be strictly confidential and will be available only to those directly involved in the study. They will be used only for purposes related to the study. Q17: How much longer will the study continue? The study will continue until the required numbers of patients have been enrolled and treated, and until all necessary visits to evaluate the efficacy of therapy have been completed. At the current rate of enrollment, it is expected to take approximately three more years to complete the study. Q18: When will results of the study be available? After the study has been completed and all the data have been analyzed, we anticipate publishing the results in a peer-reviewed scientific journal and elsewhere. We will also make the information available on the NIAID Web site (www.niaid.nih.gov).

Part 2 The "intramural" study: ----------------------- Chronic Lyme Infection Study Lyme disease is the leading vector-borne disease in the United States. Initially associated with arthritic symptoms in children, Lyme disease is now known to be a complex and potentially chronic multisystem infection caused by the spirochete Borrelia burgdorferi. But even today important questions relating to Lyme disease remain. Researchers at NIAID are undertaking a new study to investigate whether persistent signs and symptoms of Lyme disease, especially the neurologic ones (neuroborreliosis), are due to ongoing infection or to other pathogenic mechanisms. Protocol: 96-I-0052 Eligibility Criteria: Patients and controls must have documented positive serology (ELISA or IFA tests) for Lyme disease, confirmed by Western blot. Participants must meet the following requirements: Male or female between 13 and 65 years of age; Persistent symptoms and/or signs of neurologic dysfunction for at least three months; Taking no antibiotic therapy for one month prior to enrolling in the study. To help us understand Lyme disease, we are also enrolling men and women aged 18 to 65 in the following categories: Persons diagnosed with Lyme arthritis; Persons who have recovered from Lyme disease after antibiotic treatment; Persons who are seropositive for Lyme infection but have never had symptoms or antibiotic therapy for Lyme disease. Study Design: Volunteers will undergo an initial evaluation at NIH's research hospital, which will include routine laboratory tests and repeat blood tests for Lyme disease. Further evaluation will include neuropsychological tests, brain scan, lumbar puncture, leukapheresis and audiologic examination. This group of tests will take an estimate 3 to 5 days. Patients with neuroborreliosis that meet specific criteria will be offered antibiotic therapy. Treatment will be given on an outpatient basis, under the supervision of the patient's own physician. Patients will return to NIH for reevaluation at the end of therapy and over the course of one year. All study-related tests and treatment at the NIH are free. NIH will also covers the participant's travel costs to and from Bethesda. Volunteer controls for this study will receive financial compensation. Contacts: Physicians and volunteers who wish to receive further information may call 1-800-7725464 ext. 605 or write to: NIAID Chronic Lyme Disease Study Building 10 Room 11N228 10 Center Drive MSC 1888 Bethesda MD 20892-1888 FAX 301-4967383 Chronic Lyme Infection Study http://www.niaid.nih.gov/dir/labs/LCI/lyme.htm ----- NIAID: Research on Chronic Lyme Disease, NIAID Fact Sheet Research on Chronic Lyme Disease In parts of the United States, the most common tick-borne disease is Lyme disease. This emerging infectious disease is caused by a spirochetal (spiral-shaped) bacterium, Borrelia burgdorferi. Lyme disease usually is treated successfully in the early stages with antibiotics. Patients who go untreated or who do not respond to antibiotics may develop a chronic multi-system disease with an unpredictable array of symptoms. Many of these symptoms mimic those of other diseases. Chronic Lyme disease most often produces persistent arthritis or nervous system problems, although the heart also can be involved. Lyme arthritis usually affects one or several large joints, often the knee. If the central nervous system is involved, symptoms may include headaches, nausea and vomiting, memory loss and a variety of other cognitive, behavioral and sleep problems. Involvement of the peripheral nerves can result in radiating pain in the limbs, numbness and partial paralysis. No one knows why in some patients with late Lyme disease symptoms eventually diminish or disappear, whereas in other patients the symptoms persist. Scientists think that in some cases the spirochete may evade the immune system. It then survives in numbers too low to be detected by conventional tests, yet high enough to produce illness. Some scientists speculate that ongoing infection may even be caused by a second tick-borne pathogen. Persistent symptoms also may be the result of an overactive immune response that continues to injure the host=92s tissues long after the organism has been eradicated. Continued research is essential to making progress against this disease. Since 1981, when NIAID scientists first isolated the responsible organism, the Institute has supported an active research program on Lyme disease. Much of this research focuses on the pathogenesis, or disease process. This includes the study of the biology of B. burgdorferi, how it evades the immune system, how it interacts with its human host, its genetic components that allow the organism to control surface protein expression, and differences in human genes that account for the variations in the immune response among individuals. There is no uniformity among laboratories that perform tests to detect antibodies in the serum of the blood, contributing to the misdiagnosis of Lyme disease. To overcome this problem, NIAID staff met with officials of the Centers for Disease Control and Prevention (CDC) in the fall of 1994 to discuss standardization of the Western Blot diagnostic test. Guidelines for laboratories that perform and interpret serologic tests were developed and a summary was published in the CDC=92s Morbidity and Mortality Weekly Report (MMWR). Further improvements in existing tests, as well as the development of new technologies to diagnose Lyme disease remain an Institute priority. Since 1994, NIAID has convened meetings to address the issues surrounding chronic Lyme disease. Attending were scientists involved in Lyme disease at NIH and elsewhere, physicians and patient advocates. The participants acknowledged that determining whether chronic Lyme disease is caused by persistent infection or is a post-infectious disorder is a major research goal. Finding the answer to this question for any individual patient will have an important bearing on his or her treatment. While the participants acknowledged the difficulties in carrying out clinical trials to evaluate chronic Lyme disease, they agreed that clinical trials are necessary to resolve questions about optimal treatment. Participants agreed that the first trial should focus on a well-defined patient population with probable B. burgdorferi infection that might respond to antibiotics. Patients could then be selected on the basis of relapse or non-response following appropriate treatment for early-stage Lyme disease. This would provide common criteria for studying and treating this multi-symptom disease. Such patients might include (1) those with persistent arthritis or persistent fatigue or fibromyalgia; (2) those with cognitive abnormalities, neuroradiculitis, headache or encephalomyelitis; and (3) those with objective evidence of continuing B=2E burgdorferi infection. The group discussed possible clinical trial designs for assessing the effectiveness of antibiotic therapy for the treatment of chronic Lyme disease. A Request for Proposals (RFP) reflecting this discussion was issued to solicit proposals for conducting placebo-controlled studies in that regard. After rigorous review of all proposals submitted, this five-year initiative is now under way and involves several collaborating institutions. Another closely related study also is being funded by means of a research grant. Additionally, NIAID and other NIH scientists have launched a separate intramural study to better characterize and treat ongoing Lyme disease. Researchers from both studies will work closely together with the NIAID Project Officer and under the guidance of an advisory panel of Lyme disease scientists, medical experts, and patient representatives. Meanwhile, NIAID continues to pursue the underlying mechanisms of B. burgdorferi infection through grants to study immune response to Lyme disease infection and vaccination, and contracts to study animal models of chronic Lyme disease. These efforts will ultimately advance our understanding of chronic Lyme disease and lay the groundwork for future clinical trials. NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis and other infectious diseases as well as allergies and immunology. Prepared by: Office of Communications and Public Liaison National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 20892 Public Health Service U=2ES. Department of Health and Human Services May 1997 Research on Chronic Lyme Disease, NIAID Fact Sheet (May 1997) http://www.niaid.nih.gov/factsheets/lyme.htm ----- [NIH Clinical Research Studies] Protocol Number: 96-I-0052 [Active Accrual, Protocols Recruiting New Patients] Title: A Comprehensive Clinical, Microbiological and Immunological Assessment of Patients with Suspected Chronic Lyme Infection and Selected Control Populations Number: 96-I-0052 Summary: Lyme disease has emerged as the leading vector-borne disease in the United States. Despite how much has been learned about Lyme borreliosis in the past decade, there are still many remaining areas of uncertainty. One fundamental question is whether persistent signs and symptoms of disease, despite the administration of what is currently considered to be adequate antibiotic therapy, are due to ongoing active borrelial infection, to a post-infectious syndrome, to irreversible sequelae of earlier tissue injury or due to a condition unrelated to Lyme disease. Reliable objective markers of infection, of clinical status and of host responses to the organism are required to discern the scope and the implications of persistent borrelial infection, the effectiveness of current treatment options, and the development of new therapeutics approaches. The goal of this study is to assemble a well characterized cohort of patients with presumed chronic Lyme disease and relevant controls that will yield a prospective database upon which stringent diagnostic criteria can be established and future therapeutic trials can be designed. Sponsoring Institute: National Institute of Allergy and Infectious Diseases (NIAID) Recruitment Detail Type: Active Accrual Of New Subjects Gender: Male & Female Referral Letter Required: No Population Exclusion(s): None Eligibility Criteria: NEUROBORRELIOSIS PATIENTS Age 13 to 65. Persistent symptoms and/or signs of neurologic problems for at least three months, with no other documented explanation. Positive serum antibodies to B. burgdorferi documented by ELISA or IFA and confirmed by IgG Western blot. LYME ARTHRITIS Age 18 to 65. Have continuous joint swelling for more than three months, without any other cause being documented. Positive serum antibodies to B. burgdorferi documented by ELISA or IFA and confirmed by IgG Western blot. RECOVERED CONTROLS Age 18 to 65. Had Lyme disease, fulfilling the CDC Case Definition. Positive serum antibodies to B. burgdorferi documented by ELISA or IFA and confirmed by IgG Western blot. Received accepted antibiotic treatment for Lyme disease and is currently asymptomatic. SEROPOSITIVE CONTROLS Age 18 to 65. Positive serum antibodies to B. burgdorferi documented by ELISA or IFA and confirmed by IgG Western blot. No symptoms, and recall no episodes of disease compatible with Lyme infection, and have not received antibiotic therapy for Lyme disease. HEALTHY VOLUNTEERS Healthy male or female age 18-65. No history compatible with acute or chronic Lyme disease. Negative ELISA or IFA test for serum antibodies against B. burgdorferi. Weight greater than 70 lb (35 kg). No pregnant, lactating, or women with childbearing potential who are sexually active and unwilling to use effective contraception. No clinically significant laboratory abnormalities. No serious pre-existing or concurrent chronic medical or psychiatric illnesses other than Lyme disease. No past history of significant head trauma, alcohol or substance abuse in the past 5 years or other medical illness that might produce neurologic deficit (such as cerebrovascular disease). No use of systemic antibiotics in the previous month. Other medications will be evaluated in a case-by-case basis. Special Instructions: After an initial evaluation, patients will be followed either as an outpatient or be hospitalized in the Clinical Center. During the evaluation, a series of tests will be done. We would appreciate the patients to undergo as many of the tests as possible. We expect that the whole test battery can be completed in three to five days. These tests include a full clinical examination by a physician, leukapheresis (or a large blood draw of 100 cc), a spinal tap (lumbar puncture), blood drawing, skin test, magnetic resonance imaging of the brain (MRI), neuropsychologic testing and hearing examination. Healthy volunteers, Lyme arthritis, recovered and seropositive controls will be paid the established NIH daily rates for participation in particular aspects of the protocol. Patients with chronic neuroborreliosis will not receive payment for their participation in this study. Disease Category: Infectious and Parasitic Keywords: Central Nervous System Lyme Disease Borrelia Burgdorferi Neuroborreliosis Chronic Infection Recruitment Keywords: None Investigational Drug(s): None Investigational Device(s): None Contacts: Patient Recruitment and Public Liaison Office, CC. Building 61 10 Cloister Court Bethesda, Maryland 20892-4754 Long Distance Calls: 1-800-411-1222 Fax: (301) 480-9793 Electronic Mail:prpl@mail.cc.nih.gov Citations: Scrimenti. 1970. Erythema cronicum migrans, Arch Dermatol, Vol. 102, p. 104 Steere. 1977. Lyme arthritis: an epidemic of oligoarticlar arthritis in children and adults in three Connecticut communities, Arthritis Rheum, Vol. 20, p. 7 Steere. 1977. Erythema chronicum migrans and Lyme arthritis, Ann Intern Med, Vol. 86, p. 685 [Active Accrual, Protocols Recruiting New Patients] If you have: * Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC. * Questions about specific studies, or the database in general, please contact the Protocol Coordination Service Center, CC. * Technical questions regarding the Clinical Center web site, please contact the Information Systems Department, CC. Warren Grant Magnuson Clinical Center (CC) National Institutes of Health (NIH) Bethesda, Maryland 20892. Last update: 03/15/99 Clinical Study: 96-I-0052, A Comprehensive Clinical, Microbiological and Immunological Assessment of Patients with Suspected Chronic Lyme Infection and Selected Control Populations http://clinicalstudies.info.nih.gov.._96-I-0052.html ----- Original NIH release: A NEW NIH INTRAMURAL-EXTRAMURAL COLLABORATIVE STUDY OF CHRONIC NEUROBORRELIOSIS Introduction Lyme disease is the leading vector-borne disease in the United States. In 1994, more than 13,000 cases of Lyme disease were reported to the CDC, 58% more than the prior year. However, the full range of disorders associated with Lyme disease is not certain, and there are particular problems in diagnosing individuals without classical symptoms. The lack of definitive diagnostic technique for certain forms of Lyme disease has hampered our ability to answer important questions, particularly regarding persistent forms of this disease. We need objective markers of infection, of clinical status and of host responses to the organism to discern the scope and the implications of persistent borrelial infection; as well as to assess the effectiveness of current and new treatment options. One fundamental question that we face is whether persistent signs and symptoms of disease, especially neurologic ones, are due to ongoing active borrelial infection or due to other pathogenic mechanisms. In collaboration with investigators at leading Lyme centers, NIAID has initiated a new clinical research study, with the goal to help answer this question. We will assemble and characterize patients with presumed chronic Lyme disease and relevant controls. The comprehensive study of these groups should yield a prospective database upon which diagnostic criteria can be established and future therapeutic trials can be designed. Study Design: This study is divided in two parts. In the first part, we will compare results of several different eveloving tests for Borrelia burgdorferi infection between patients with suspected chronic neuroborreliosis and various control groups. The goal is to identify objective parameters that could be used to substantiate and follow the persistence of infection in these and other patients. We are also evaluating the extent of infection and the immune response to it in patients with neuroborreliosis and other persons exposed to B. burgdorferi who haven't been treated. We will study patients with chronic neuroborreliosis, patients with Lyme arthritis, persons who recovered from Lyme disease wfter therapy, and persons incidentally found be seropositive for B. burgdorferi who haven't been treated. d. The groups of subjects will be compared with patients with multiple sclerosis and normal volunteers. All patients and controls, with the exception of the multiple sclerosis patients and normal volunteers, must have documented positive serum antibodies B. Burgdorferi by ELISA or IFA, confirmed by Western blot. Chronic Neuroborreliosis Patients: male or female, age 13 to 65 Persistent symptoms and/or signs of neurologic dysfunction for at least three months, with no other documented explanation for their signs and symptoms; Taken no antibiotic therapy for one month prior to enrolling in the study. Controls: To help us better understand Lyme disease, we also are enrolling men and women aged 18 to 65 in the following categories: Persons diagnosed with Lyme arthritis, who have continuous joint swelling for more then three months with no other documented cause; Persons who have had Lyme disease, according to the CDC Lyme Disease National Surveillance Case Definition, received accepted antibiotic treatment for Lyme disease, and are currently asymptomatic; Persons who are seropositive for Lyme infection but are asymptomatic, recall no episodes of disease compatible with Lyme infection, and have not received antibiotic therapy for Lyme disease. Persons who have serious pre-existing or concurrent chronic medical or psychiatric illnesses are excluded from the study. The evaluation will include full clinical and neurological evaluation, routine laboratory tests, B. burgdorferi EIA or ELISA (with confirmatory immunoblot), Babesia and Ehrlichia screening, lumbar puncture, high-resolution MRI, audiologic evaluation, neuropsychological testing and leukapheresis for extensive immune system studies. This group of tests will take an estimated 3 to 5 days. In the second part of this study, patients with clinical suspicion of chronic neuroborreliosis who have evidence of persistent infection by PCR, antigen-capture assay or other assays will be offered four weeks of intravenous ceftraxone therapy. The therapy will be given on an out-patient basis, ideally under the supervision of each referring physician. The subjects will then return to NIH for reevaluation at the end of treatment, three, six, and twelve months after therapy. All costs of the study and medical care at the NIH and travel to and from Bethesda will be assumed by the NIH. The volunteers controls will receive financial compensation for the time and inconvenience of participating in this study. The evaluations will be performed at the Warren Grant Magnuson Clinical, a 14-story 470-bed hospital that is part of the NIH in Bethesda, Maryland, just outside Washington, D.C. The hospital portion of the Clinical Center is especially designed for medical research. Patients are admitted to the Clinical Center on referral by their physician and only for research purposes. These patients receive study-related clinical care, and contribute to a better understanding of the disease. We are convinced that this type of multi-disciplinary, prospective study is the most effective way to approach the complex issue of chronic neuroborreliosis. This study developed in collaboration with scientists in NlAlD's intramural and extramural programs, in the National Institute of Neurological Disorders and Stroke (NINDS), in the National Institute on Deafness and Other Communication Disorders (NIDCD), in the National Institute of Mental Health (NIMH) and with leading Lyme disease specialists at SUNY at Stony Brook, New England Medical Center, the Mayo Clinic and others. It is our hope that these initial studies involving carefully selected patients will provide new information about chronic Lyme disease and suggest additional avenues for patient care and research. We realize that the patient group we are starting may represent only the apex of a pyramid of illnesses potentially related to B. burgdorfi infection. However, the intention in this first study is to develop firm answers for one well-defined patient group that might eventually be applicable to others. If you have patients who may want to participate and are eligible for this research protocol, or if you would like to receive further information about this research protocol, please contact: NIAID Chronic Lyme Disease Study Building 10 Room 11N228 9000 Rockville Pike Bethesda MD 20892 1-800-7725464 ext. 605 FAX(301) 4967383 Project Staff: Adriana Marques, M.D., Principal Investigator Brenda Cucherinni, Ph D., N.P., Co-lnvestigator Stephen E. Straus, M.D., Project Director NIH COLLABORATIVE STUDY OF CHRONIC NEUROBORRELIOSIS http://changes.net/nihres.htm or http://www.x-l.net/Lyme/nihres.htm ----- NIAID Sources Sought Announcement CLASSCOD: A--Research and Development--Potential Sources Sought OFFADD: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Contract Management Branch, Solar Bldg., Room 3C07, 6003 Executive Blvd. MSC 7610, Bethesda, MD 20892-7610 SUBJECT: A--CHRONIC LYME BORRELIOSIS CLINICAL TRIAL SOL N01-AI-65296 DUE 110498POC Mr. Carl Henn, Contracting Officer, 301-496-0993 DESC: The National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases, is seeking sources capable of conducting randomized, placebo-controlled, double-blind clinicals trials to demonstrate the efficacy of treatment with intravenous ceftriaxone (2 grams per day for 30 consecutive days) followed by oral doxycycline (200 mg per day for 60 consecutive days) for the treatment of chronic Lyme borreliosis. The trials will involve defined cohorts of patients, from regions of the United States in which Lyme disease is endemic, that are either seropositive or seronegative for Lyme disease (by the two-test CDC-Dearborn criteria) at the time of enrollment, and who meet the inclusion and exclusion criteria established and approved for this study. Primary analysis of the efficacy of the antibiotic therapy used 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; however, they will not be used for primary analysis of efficacy. The SF-36 Health Survey (and additional MOS measures) will be administered to study participants five times: at baseline (prior to therapy); at one month (the end of intravenous therapy); at three months (the end of intravenous and oral therapy); at six months; and at one year . Also, at baseline and at defined intervals (as stipulated in the protocol approved for use in these studies),specimens will be collected to test for: (a) an immune response to Borrelia 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 (e) serum antibodies specific for possible co-infecting agents, e.g., Babesia microti and Ehrlichia species. Interested parties should submit, no later than November 4, 1998, four (4) copies of a capability statement addressing each of the areas outlined above. The statement also should include information on numbers of eligible volunteers likely to be enrolled per year (do not provide the names of prospective volunteers or personal identifiers). A copy of the specific inclusion and exclusion criteria approved for the study will be provided on request. This Sources Sought Announcement is a request for information to assist the NIAID in selecting additional sites for conducting the studies described. It may or may not result in a solicitation. Respondants are invited to discuss additional terms or conditions with the NIAID by contacting: Carl Henn Contracting Officer Contract Management Branch National Institute of Allergy & Infectious Diseases National Institutes of Health Solar Building, Room 3C02 6004 Executive Blvd., MSC 7630 Bethesda, MD 20892-7630 Telephone: (301) 496-0993 FAX: (301) 480-5253 E-mail: ch24v@nih.goc NIAID Sources Sought Announcement http://www.niaid.nih.gov/contract/notices/note1007.htm

PART 3 The "extramural" study: ----------------------- NIH Chronic Lyme Disease Treatment Study Protocol Sponsor: National Institutes of Health National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases Clinical Studies in Chronic Lyme Disease Contract No. N01-AI-65308 Principal Investigator: Mark S. Klempner, M.D. Coordinating Center: New England Medical Center Boston, Massachusetts Clinical Centers: New York Medical College Valhalla, New York Yale university School of Medicine New Haven, Connecticut Protocols: 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. A Phase III, randomized, double-blind, placebo-controlled, multicenter trial of the safety and efficacy of ceftriaxone and doxycycline in the treatment of seronegative chronic Lyme disease. Purpose of this Research Study This research study is being conducted to determine if treatment for a long period of time, with the antibiotic drugs ceftriaxone and doxycycline, helps patients with chronic Lyme disease. Lyme disease is caused by the bite of an infected tick. Most people who get Lyme disease are cured with standard antibiotic treatment. Some people however, do not get well after standard treatment. They have continuing (chronic) problems such as pain in their joints or muscles, or problems with their concentration or memory. For persons who have had Lyme disease and have received the standard treatment and have not gotten well, there is a possibility that they have chronic Lyme disease. This study is designed to see if giving more antibiotic will cure chronic Lyme disease and to test for improvement of its symptoms. Background Information Lyme disease Lyme disease is an infection which spreads throughout the whole body. The disease begins when a type of bacteria called Borrelia burgdorferi enters the skin when a person is bitten by an infected tick. The bacteria can spread through skin and blood to reach parts of the body far from the tick bite. A very common sign of early, active Lyme disease is a rash which grows larger and larger in the rough shape of a circle. Other symptoms of early disease can include fevers, muscle and joint pains and joint swelling. Treatment with antibiotics at the beginning of Lyme disease is very effective at killing all of the bacteria and ending the symptoms. Unfortunately, some patients with Lyme disease who are treated sometimes develop symptoms which don't go away. These symptoms can include arthritis, nerve pains, concentration and memory problems. Some people with these continuing symptoms have gotten better when they were given antibiotics and some have not. The ones who do not get better are the patients referred to here as chronic Lyme disease patients. At this point, it is not clear whether those patients who have chronic Lyme disease are helped by receiving higher doses, longer treatment, or different antibiotics. Description of this Research Study This research study is being conducted under a contract from the National Institute of Allergy and Infectious Diseases which is part of the National Institutes of Health. It will take place at three hospitals, New England Medical Center in Boston, Massachusetts and New York Medical college in Valhalla, New York, and Yale University School of Medicine in New Haven, Connecticut. Persons enrolled will be followed for one year. The study will last for 5 years. This is a randomized research study. This means that half of the patients in this research study will be given ceftriaxone and doxycycline antibiotics. The other half of the patients will be given identical appearing placebos, which are sterile solutions and pills that appear identical to the antibiotics but contain no active drug. Neither the patient nor their doctors will know which one they receive. This is to prevent the knowledge of which drug is being given from changing the results of the study. There is a 50/50 chance that a patient will get the ceftriaxone and doxycycline antibiotics. The study will measure the effects of giving 30 days of I=2EV. (intravenous) ceftriaxone followed by 60 days of oral doxycycline to patients with chronic Lyme disease. A person may participate in this study only if they have a positive blood test for Lyme disease or a skin rash that is typical of early Lyme disease (erythema migrans) documented by a physician in the past, have been previously treated with antibiotics, and still have continuing (chronic) symptoms. If enrolled, there will be an initial evaluation at one of the study medical centers. Treatment will then take place at home with intravenous and oral study drugs. Half of the patients enrolled will receive an intravenous dose (2 grams) of ceftriaxone once per day. The other half of the patients enrolled will receive an identical appearing sterile solution, with no drug, once per day intravenously. At the end of the 30 day intravenous therapy, the patients who were receiving the ceftriaxone will receive 60 days of doxycycline which will be taken in pill form (100mg.), twice a day. Those who did not get the ceftriaxone will take pills which are identical in appearance to the doxycycline but contain no drug. Patients will be assigned to each group randomly. Neither the patient nor his/her physician will know which group a patient is in. In order to qualify for participation in this research study, a blood test for Lyme disease must first be performed. Results of this test take about 1 week to determine. If test results meet the requirements for participation in the study, patients will be asked to return to the medical center for additional testing. At that time, they will be given a complete physical examination. A small amount of blood, (approximately 10 tablespoons) will be drawn. Additional blood samples will be drawn at home on days 3, 5, 13, 21, 30, 45, and 75. Women of childbearing age will be given a urine test for pregnancy. Urine samples for other testing (2 tablespoons) will be collected from all patients initially, and at home on days 3, 5, 13, 21, 30, 45, and 75. Patients with chronic Lyme disease may have infection of the spinal fluid. A lumbar puncture (spinal tap) will be performed on all patients who enter the study. This will be done by a licensed, experienced physician. The lumbar puncture will involve placing a small amount of local anesthetic in the lower back and then placing a small needle between the vertebrae (bones of the spine) and withdrawing a small amount (about 3 tablespoons) of spinal fluid. Patients who have abnormal spinal fluid will have a second lumbar puncture at the completion of the study. Portions of all samples collected will be stored at New England Medical Center for future research in chronic Lyme disease only. Samples will be identified by code. No personal identification will be included in sample labeling. Those with symptoms of numbness, tingling or nerve pain will be tested to evaluate nerve function. This testing will include Nerve Conduction Studies and Electromyography. Nerve Conduction Studies are performed first and take about 30-45 minutes. Patients will be asked to lie down and small electrical connections will be taped to several skin sites. A small electrical signal is sent through the connection to the skin and the response of the skin or the muscles beneath is measured. These electrical signals feel like a small shock andare almost alwayswell tolerated. Electromyography is performed next and takes a total of 5-10 minutes. During this test, a small needle (smaller than the needle used during blood drawing) is placed in one or more muscles in the arm, leg or back. Electrical activity in the muscle is measured when the muscle is at rest and again when it is flexed. Placement of the needles may be slightly painful, but no electrical signals are delivered through the needles. The test lasts 30-60 seconds per muscle. Information gained from these two tests is then analyzed to determine if there is evidence of nerve or muscle disease. Patients will be tested again at 180 days. Finally, Patients will be given a series of special tests which are designed to measure whether there has been any change in normal thinking abilities and how their symptoms affect your their functioning. These tests include measurements of concentration, memory, language, and overall sense of physical and emotional well being. These tests will take about 2 =BD hours to complete. All of these tests will be repeated on day 90 to measure any change after treatment. A few will be repeated on days 180 and 360. Initial evaluations will require approximately 4 hours at the medical center. Evaluations at 30 and 90 days will require approximately 2 hours at the medical center. Repeat testing at 180 days will require 2-6 hours depending on which symptoms of chronic Lyme disease are being reassessed. Evaluations of the initial test results must occur before patients can be assigned to a group for this study. After initial evaluation, they will go home. Once the test results have been evaluated, they will be contacted by study personnel and an appointment will be made for them to return to the medical center. They will have an intravenous catheter placed in a vein of their arm. This involves washing the skin with disinfectant, perhaps shaving some of the hair in a small area, placing a small needle into a vein, threading a small sterile plastic tube over the needle and withdrawing the needle. The tube is then secured in place with adhesive tape and flushed with sterile water. Patients will receive their first dose of study drug under the supervision of the investigator at the medical center. At this point, they will be discharged to their home. Before leaving, patients will be instructed in self administration of pre-mixed intravenous study drug. Intravenous study drug will be delivered to their home twice during the initial 30 day period. A Registered Nurse will visit patients in their home every other day during the period of time that they are receiving the intravenous study drug. The nurse will measure vital signs, (blood pressure, heart rate, breathing rate) draw any blood samples that are needed, and check the intravenous catheter site. They will also continue to instruct patients on any aspect of study drug self administration. Side Effects / Risks Ceftriaxone Ceftriaxone is an antibiotic that has been used widely in the treatment of severe bacterial infections. It is very effective in killing the Lyme disease bacteria in the laboratory and it is effective in treating patients with severe new Lyme disease infections. Ceftriaxone will be given in I.V. (intravenous) form for one month. The advantage of ceftriaxone over other antibiotics is that it lasts in the bloodstream for a longer period of time. This means it needs to be given only once a day. Ceftriaxone is also better at penetrating into areas of the body that are difficult to reach such as the central nervous system or joints. Ceftriaxone has been shown to be very safe given at these doses in a large number of patients. The major side effects include rash (in about 1=2E7% of all cases), diarrhea (2.7%), changes in liver function (approximately 3%) and gallstones (less than 1%). Liver function will be monitored during the study. Ceftriaxone is related to penicillin and a small percentage of patients with penicillin allergies will have allergic reactions to ceftriaxone(5-8%). Patients with allergies to penicillin should inform the investigator prior to study entry. Although ceftriaxone has not been documented to cause harm to a fetus or an embryo, there have been no studies to document its safety in pregnancy. Patients should inform the investigator if they become pregnant at any point before orduring theadministration ofceftriaxone. Doxycycline Doxycycline is an antibiotic that is commonly used in the treatment of a wide range of infections including Lyme Disease. Doxycycline will be given in oral (pill) form, twice a day for two months, after finishing the treatment with intravenous ceftriaxone. Doxycycline has also been shown to be very safe in the dosages being prescribed in this study. Reported side effects include photosensitivity (exaggerated sunburn), rash, gastrointestinal upset, changes in liver (rarely) and kidney function. Doxycycline is known to harm unborn babies and may cause birth defects. It should not be taken during pregnancy. Patients should immediately inform the investigator if they become pregnant at any point before orduring the administration of doxycycline. Intravenous Catheterization An intravenous catheter will be placed in a patient's arm for the duration of the treatment with study drug (30 days). There is a risk of infection with any intravenous catheter and you must maintain it carefully . Catheter infections are usually treated by removal of the catheter, either with or without additional antibiotics. Catheter infections which are left untreated may progress to involve the skin surrounding the catheter, the bloodstream and sites distant from the catheter. Generalized infection resulting from untreated catheter infections can be fatal. Patients must inform the investigator immediately if there are any signs of infection of the catheter (redness, pus, tenderness). The catheter site will be monitored closely by the investigators and the study nurses. Lumbar Puncture The lumbar puncture is a safe procedure in healthy patients as well as in patients with Lyme disease. The most common side effect following a lumbar puncture, occurring in approximately 2-10% of patients undergoing this procedure, is a headache which may persist from 1 to 5 days (considerably longer in rare instances). The leakage of spinal fluid is suspected of causing post-LP headaches. The risk of headache can be reduced by lying flat in bed for 24 hours following the procedure. In the case of a prolonged post-LP headache--i.e. a headache that lasts more than 2-3 days-- treatment with a blood patch may be employed. This treatment involves the withdrawing of a small amount of blood from a vein which is then injected at the site of the lumbar puncture to provide a seal and prevent further leakage of spinal fluid. There is also a small chance of having an allergic reaction to the local anesthetic. If you have had prior reactions to anesthetics, you must inform the investigator. Lastly, there is a small chance of developinginfection followinglumbar puncture. Blood Drawing Blood will be drawn at various times during the study. This procedure involves a small amount of discomfort as a needle is placed in a vein and blood is withdrawn into test tubes. There is a small risk of infection as well as a small possibility of bruising around the site. Pregnancy For women, a pregnancy test will be performed which must be negative before enrollment in the study. If a woman becomes pregnant at any time during, or for 1 month after the period of drug administration, the study drugs used in this research study may cause harm to her unborn baby or cause birth defects. The use of doxycycline (a tetracycline), one of the two antibiotics patients may receive by participating in this study, is known to cause discoloration (yellow-gray) of the teeth in children if their mother took the drug during the last half of pregnancy. In addition, there is evidence of toxic effects to embryos when tetracyclines have been administered to pregnant animals. Therefore, it is important that women are not pregnant nor plan to become pregnant during the course of the study. If a woman chooses to participate, she must use adequate birth control (e.g. barrier method, oral or implant contraceptive or abstinence) to prevent pregnancy during this study. Should a female patient become pregnant at any time during this study, she must immediately notify her physician and study personnel. She will be discontinued from the study and she will be followed by study personnel. Benefits We do not know if ceftriaxone and doxycycline will be effective against chronic Lyme disease. Patients in both groups will receive all of the testing necessary to evaluate the disease and its progress. Participation in this study will afford patients the possibility of treatment which may be effective in resolving the symptoms of chronic Lyme disease. If at any time a patient's condition changes so that the participation in this study is no longer in their best interest, the treatment will be stopped and a new plan will be discussed. If a more effective treatment becomes available, doctors will discuss this new alternative with patients. If, at the completion of the study, the protocol treatment is found to be effective, and a patient has received the placebo, they will be offered the study treatment regimen (30 days of intravenous Rocephin, 2 grams per day, followed by 60 days of oral doxycycline, 200mg per day) through their regular health care insurance coverage. If coverage for treatment is denied by regular health care insurance, or if a patient does not have health insurance, the costs of such treatment will be paid through the contract supporting these studies. Alternatives A person may choose not to participate in this particular study. Various other treatment options are available through personal physicians; however, there are currently no proven effective treatments for chronic Lyme disease. If a person chooses not to participate in this research study, their decision will not affect any future care they may receive at these institutions. Confidentiality Representatives of the United States Food and Drug Administration (FDA), the National Institutes of Health (NIH, sponsor of the study), and the manufacturers of the drugs may inspect patient records. Information gained from the study will be reported to the NIH, FDA, and perhaps other regulatory authorities. When results of a study such as this are reported in the medical journals or at meetings, identification of those taking part is withheld. Medical records of patients are maintained in confidence according to current legal requirements. They are made available for review to authorized users only under the guidelines established by the Federal Privacy Act. Patient Costs Costs directly relating to the study (blood tests, antibiotics,intravenouscatheterization,lumbar puncture, EMG) will be covered by the study. More Information For more information, please call the Chronic Lyme Disease Study toll free phone line at 888-596-3287 and leave your name and phone number and you will be contacted by study personnel or call Mr. Gary Johnson, Clinical Trials Manager at 617-636-4893. NIH Chronic Lyme Disease Treatment Study Protocol http://www.niaid.nih.gov/dmid/lymeprotocol.htm ----- Seropositive Chronic Lyme Disease 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=92s 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). For additional information, click here to go to the Chronic Lyme Treatment Study Web site maintained by the New York Medical College. Seropositive Chronic Lyme Disease http://www.niaid.nih.gov/recruit/phsiiip.htm ----- Seronegative Chronic Lyme Disease A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of the Safety and Efficacy of Ceftriaxone and Doxycycline in the Treatment of Seronegative 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 seronegative 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 seronegative 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=92s 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). For additional information, click here to go to the Chronic Lyme Treatment Study Web site maintained by the New York Medical College. Seronegative Chronic Lyme Disease http://www.niaid.nih.gov/recruit/phsiiin.htm

PART 4, Carl Brenner "explains" the Study: Chronic Lyme Treatment Study Web site, New York Medical College http://www.nymc.edu/lyme -------------- Other information on the NIH chronic Lyme disease study: NIH Chronic Lyme Study An Explanation by Carl Brenner Although significant advances in Lyme disease research have occurred over the last two decades, little progress has been made in understanding the etiology of and proper treatment for chronic Lyme disease symptoms. Are lingering symptoms after "appropriate" antibiotic therapy due to persistent infection, a derangement of the immune system, slowly resolving disease or permanent tissue damage? Is it possible that these phenomena occur in combination in some patients? The answers to these questions have profound implications for the treatment of chronic Lyme disease; therefore, it is important that they be aggressively pursued. Unfortunately, this is a research area that Lyme disease investigators have historically shied away from. There is hope on the horizon, however. In early 1994, in response to a directive from Congress, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on the NIH campus to review issues relating to chronic Lyme disease. In attendance were about a dozen academic Lyme disease researchers, several representatives from government health agencies and a handful of Lyme disease clinicians and patient advocates. At the meeting, attendees discussed ways to improve the diagnosis and treatment of chronic Lyme disease and suggested specific research directions for future studies of the subject. Later in the year, another meeting was held, with additional participants in attendance, to explore study designs for possible clinical investigations of chronic Lyme disease. As an outcome of these consultations, NIAID issued a request for proposals (RFP) to the academic Lyme disease research community in 1995. Two research groups responded to the RFP by submitting detailed proposals for clinical treatment trials of patients with chronic Lyme disease. Meanwhile, scientists at NIAID began designing an intramural chronic Lyme study of their own, to be carried out on the NIH campus. (This study has already begun.) Finally, in 1996 a contract was awarded to Tufts/New England Medical Center -- one of the two groups that responded to the RFP - to initiate an extramural study of patients with chronic symptoms after prior treatment for Lyme disease. Thus, the current "NIAID Chronic Lyme Disease Study" comprises two parts, one intramural and one extramural. The focus of the intramural study is on patients with chronic Lyme disease of the nervous system. Patients with neurologic infection will be rigorously tested and compared with five control groups: Lyme arthritis patients, patients with multiple sclerosis, recovered Lyme disease patients, asymptomatic individuals who are seropositive for antibodies to B. burgdoreri, and finally, a group of healthy volunteers. The test battery is extremely comprehensive, and includes a complete blood workup, neurologic exam, neuropsychological testing, EKG, brain MRI, nerve conduction studies (if appropriate), HLA typing, blood lymphocyte typing, blood cytokine profiles and lumbar puncture. Spinal fluid from all patients, including the controls, will be probed for borrelial antigens, DNA and immune complexes, as well as other, more routine CSF parameters. By examining the entire study population clinically, microbiologically and immunologically, NIAID investigators hope to compile a prospective database upon which state-of-the-art diagnostic criteria for Lyme disease can be established. In addition, patients with active Lyme disease will be offered treatment through their primary care physician, and will be evaluated at NIAID at periodic intervals thereafter. The extramural study will focus on a different patient population. Although objective manifestations of Lyme disease usually resolve after antibiotic treatment, it is well recognized that a significant percentage of patients continue to suffer from persistent symptoms such as musculoskeletal pain, fatigue, memory impairment, numbness and tingling despite "appropriate" antibiotic therapy. Considerable controversy exists over whether these symptoms are due to persistent infection with B. burgdorferi, and if so, whether they are responsive to additional treatment. In the extramural portion of the Chronic Lyme Study, patients with these manifestations of chronic Lyme disease after previous treatment will be enrolled in a double-blind placebo-controlled trial of the efficacy (and safety) of three months of additional antibiotic therapy. The antibiotic regimen selected by the investigators is intravenous ceftriaxone (2 grams a day) for one month, followed by oral doxycycline (200 mg/day, given in doses of 100 mg every 12 hours) for two months. In a placebo-controlled study, patients are randomized in a 1:1 ratio to receive either active drug or placebo. Thus, half the patients in this study will receive antibiotic and half will receive dummy medications that are usually indistinguishable from the real thing. Because the study is double-blinded, neither the patients nor the investigators will know which patients are getting what. This will insure that the results of the study are unaffected by physician or patient expectations. The primary outcome measure will be the patients' own self-ratings six months after the initiation of treatment on a frequently employed, previously validated, written health survey form. Having patients rate themselves is another important tool for eliminating possible physician bias in evaluating patient progress, or lack thereof. During the period during which either antibiotics or placebo are being administered, the study scientists will collect multiple blood and urine specimens from patients for repeated probes for borrelial DNA by PCR (in blood) and borrelial antigens (in urine). In addition, all patients will be screened for possible co-infection by other tick-borne pathogens, such as ehrlichia and babesia. Finally, neuropsychological testing will be employed on all patients in the study, both before and after treatment, to provide measures of immediate and delayed memory, conceptualization, language and attention. All of these measurements will supplement the patient self-ratings and will provide data for correlating patient progress with objective measures of infection or cognitive improvement. One particularly attractive facet of the extramural study is that it will examine both seropositive and seronegative patients. (Statistics on the two groups will be compiled separately.) Since it is well known that antibiotic treatment can abrogate the human antibody response, and since all of the patients enrolled in the study will have previously received antibiotics for their Lyme disease, it is clear that it would be both arbitrary and misguided to exclude patients based on the absence of antibodies to B. burgdoreri in their blood. The objectives of the extramural study, then, are as follows: 1.to determine whether three months of additional antibiotic therapy benefits patients with chronic Lyme disease. 2.to determine if evidence of persistent infection with B. burgdorferi can be found in patients with chronic Lyme disease. 3.to determine if evidence of co-infection with other tick-borne agents can be found in these patients. 4.to see if specific clinical or laboratory parameters improve in patients who receive antibiotics compared to patients who receive placebo. 5.to determine if specific parameters are predictive of a response to therapy should it be observed. Taken together, the intramural and extramural portions of the Chronic Lyme Study constitute a reasonable, if somewhat belated, start on the investigation of the various challenges presented by chronic Lyme disease. The exhaustive testing regimen of the intramural study should yield exciting data, particularly in the immunogenetic realm, and the extramural study's focus on patients with post-treatment symptoms (a population that has been badly neglected up to now) is very welcome. In addition, the two studies complement each other in that one focuses on patients with clear-cut infection while the other examines a population whose infectious status is unknown. Finally, currently-proposed but not yet funded studies of non-human primates will further supplement data gathered during these projects, in that they will allow researchers to have access to tissue for extensive pathology studies, and thus aid in the possible discovery of post-treatment sanctuaries for B. burgdoreri in a primate model. While no single study or group of studies is going to definitively solve all of the issues surrounding chronic Lyme disease, it is hoped that these projects will at least kick start the process. Last revised November 28th, 1998 http://www.lymealliance.org/Medical..ed22/med22.html

a_weisman@yahoo.com

Re: Some Interesting Materials on the NIH Study

PART 5

LymeNet Newsletter Volume 6 Issue 10

NIH: Chronic Lyme Borreliosis Clinical Trial RFP - NIH/ALI
Source: Carl Henn, Contracting Officer  <ch24v@nih.gov>
Release Date: 7 October, 1998
URL: http://web.fie.com/htdoc/fed/nih/ge..ny/10099808.htm

CHRONIC LYME BORRELIOSIS CLINICAL TRIAL SOL N01-AI-65296 DUE 110498
POC Mr. Carl Henn, Contracting Officer, 301-496-0993.

The National Institute of Allergy and Infectious Diseases, Division of
Microbiology and Infectious Diseases, is seeking sources capable of
conducting randomized, placebo-controlled, double-blind clinical
trials to demonstrate the efficacy of treatment with intravenous
ceftriaxone (2 grams per day for 30 consecutive days) followed by oral
doxycycline (200 mg per day for 60 consecutive days) for the treatment
of chronic Lyme borreliosis. The trials will involve defined cohorts of
patients, from regions of the United States in which Lyme disease is
endemic, that are either seropositive or seronegative for Lyme disease
(by the two-test CDC-Dearborn criteria) at the time of enrollment, and
who meet the inclusion and exclusion criteria established and approved
for this study. Primary analysis of the efficacy of the antibiotic
therapy used 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; however,
they will not be used for primary analysis of efficacy. The SF-36
Health Survey (and additional MOS measures) will be administered to
study participants five times: at baseline (prior to therapy); at one
month (the end of intravenous therapy); at three months (the end of
intravenous and oral therapy); at six months; and at one year . Also,
at baseline and at defined intervals (as stipulated in the protocol
approved for use in these studies), specimens will be collected to test
for: (a) an immune response to Borrelia 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
(e) serum antibodies specific for possible co-infecting agents, e.g.,
Babesia microti and Ehrlichia species. Interested parties should
submit, no later than November 4, 1998, four (4) copies of a capability
statement addressing each of the areas outlined above. The statement
also should include information on numbers of eligible volunteers
likely to be enrolled per year (do not provide the names of prospective
volunteers or personal identifiers). A copy of the specific inclusion
and exclusion criteria approved for the study will be provided on
request. This Sources Sought Announcement is a request for information
to assist the NIAID in selecting additional sites for conducting the
studies described. It may or may not result in a solicitation.
Respondents are invited to discuss additional terms or conditions with
the NIAID by contacting: Carl Henn Contracting Officer Contract
Management Branch National Institute of Allergy & Infectious Diseases.

LymeNet Newsletter Volume 6 Issue 10
http://www2.lymenet.org/domino/nl.n..16?OpenDocument

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Conference Abstract - April 28-30, 1997

Title:
Randomized, Double-Blinded, Placebo-Controlled, Multicenter Trials
of the Safety and Efficacy of Ceftriaxone and Doxycycline in the
Treatment of Patients with Seropositive and Seronegative Chronic LD
Authors:
Klempner M
Conference:
10th Annual International Scientific Conference on Lyme Disease &
Other Tick-Borne Disorders, National Institutes of Health,
Bethesda, MD April 28-30, 1997
Presenter:
Mark Klempner, M.D.
Tufts New England Medical Center

Abstract:
A description of the NIH supported clinical protocols for the
characterization and treatment of patients with Chronic Lyme Disease
(CLD) will be presented.
The objectives of these studies are to determine whether:
1. intensive antibiotic treatment benefits seropositive and
seronegative patients with CLD,
2. evidence of persistent infection with Bb can be found in patients
with CLD,
3. evidence of coinfection with other microorganisms can be found in
patients with CLD,
4. specific clinical or laboratory parameters improve in patients who
receive antibiotic therapy compared to patients who receive placebo,
and
5. specific parameters are predictive of a response to therapy should
it be observed.

These studies are Phase III, randomized, double-blinded, placebo-
controlled, multicenter trials (two centers). 260 patients will be
enrolled in the studies and randomized to receive either antibiotic
therapy or placebo in a 1:1 ratio; antibiotics and placebo will be
administered both intravenously and orally. The antibiotic regimen will

be intravenous ceftriaxone 2 gms/day for 30 days followed by oral
doxycycline 200mg/day for 60 days. Placebos identical in appearance to
the intravenous and oral antibiotics will be administered by the same
routes and for the same duration to patients randomized to the placebo
group. Initial and serial analyses during treatment will include PCR of

plasma and CSF for borrelia and other organism DNA, borrelia urinary
antigen, and serum antibodies to organisms transmitted by Ixodes ticks.

Primary outcome analysis for the efficacy of antibiotic therapy will be

determined by improvement in the patient's health related quality of
life as measured by the SF-36 Health Survey. Other assessments will
include changes in pain and cognition using scales from the Medical
Outcomes Study, the fibromyalgia impact questionnaire,
neuropsychological tests, and nerve conduction studies for patients
with
neuropathic pain.

Unique ID: 97LDF032


http://www2.lymenet.org/domino/abst..43?OpenDocument

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Lyme Disease Advisory Panel Summary Report - September 4, 1996

The following summary report was submitted to NIAID by the
Lyme Disease Advisory Panel, following its first meeting on
August 14, 1996. This panel was convened by the Institute to
provide advice and guidance concerning the planning of
Lyme disease clinical trials.

Lyme Disease Advisory Panel Summary Report
September 4, 1996

Introduction

The Lyme Disease Advisory Panel would like to express its
gratitude to the NIAID staff for their excellent efforts in planning
and
organizing this meeting, to the investigators for excellent and
well-prepared presentations, and to the participants for invaluable
contributions to the discussions and deliberations.

A number of deliberations and discussion items arose among the
panel members and will be subdivided to the categories of the NIH
Intramural Proposal, presented by Dr. Adriana Marques, and the
New England Medical Center Extramural Proposal, presented by
Dr. Mark Klempner. These will be referred to as the Intramural
Protocol and the Extramural Protocol, respectively.

The Panel recognizes and appreciates that the protocols reviewed
at this meeting are considered to be "in evolution" by the
investigators and considers the comments of the panel to be within
the spirit of creating the best possible final protocol.

There was a consensus among the members to have two new
individuals available to the Panel, if possible. These individuals
would be a biostatistician and a neuropsychologist.

Comments on the Intramural Protocol

Choice and Duration of Antibiotic Treatment: Considerable
discussion arose over this issue. In conclusion, the Panel agreed
with the antibiotic regimen that has been chosen by the
investigators. Therefore, no change in the choice or duration of
antibiotic treatment was recommended. The Panel encourages the
intramural investigators to discuss any post-treatment evidence of
persistent infection with both the patients and their personal
physicians, so that informed decisions can be made about the
desirability of further treatment in these patients.

Number of Lumbar Punctures: Although it was recognized that
patient compliance may be an issue, it was strongly recommended
that attempts should be made to obtain the four lumbar punctures.

Additional Laboratory Tests: It was suggested that tests based
on the detection of Borrelia burgdorferi- specific immune
complexes and the presence of B. burgdorferi antigen in urine be
incorporated in these studies.

Comments on the Extramural Protocol

Choice of Antibiotics and Duration of Therapy: The Panel
agreed with the choice made by the investigators for this initial
study, realizing that the choice may be subject to change in future
studies. They agreed that this strategy was reasonable as a
starting point, since it includes agents (antibiotics) with good
activity against B. burgdorferi, has agents with satisfactory nervous
system penetration, and includes agents which achieve
satisfactory intracellular levels. The Panel is also aware that cost,
side effects, and pharmacokinetics are important considerations in
choice of antibiotics.

Inclusion Criteria: The Panel agreed that the inclusion criteria
require documentation that the previous diagnosis of acute Lyme
disease was made by a physician. The Panel agreed with the
investigators that patients with PCR-positive evidence for the
presence of B. burgdorferi DNA in plasma or spinal fluid should be
excluded from the protocol and referred to the NIH Intramural study.

Neuropsychological Evaluation: The Panel requested
standardization of the neuropsychological tests to be used in both
the Intramural and Extramural studies.

Length of Illness Prior to Entry into the Protocol: It was
suggested that no longer than four years be allowed for the
diagnosis of Lyme disease prior to entry into this protocol.

Concomitant Infections: The importance of testing for
concomitant Ehrlichia and Babesia infections was recognized and
endorsed.

Statistical Analysis: There was considerable discussion on the
numbers of patients required to detect a significant antibiotic
treatment effect, as well as the magnitude of the placebo effect to
be expected in studies such as these. The advice of
biostatisticians with expertise on these matters will be sought to
resolve these issues.

Other issues: Compliance with the treatment protocol and use of
concomitant drugs will be monitored. The addition of audiology
competency testing was suggested for the neuropsychological
evaluation. The suggestion was made that the investigators
engage in dialogue with others also conducting clinical studies on
chronic disease.

It was suggested that the term Post-Lyme Disease Syndrome
should be replaced by Chronic Lyme Disease in the protocols
being considered.

The Panel suggested that urine antigen also be determined in the
Extramural protocol patients (see discussion under Intramural
Protocol).

The Panel felt that future studies in primate models would be highly
complementary to the proposed studies. The conducting of these
studies was considered maximally important by the Panel.

Members of DMID Advisory Panel on Clinical Studies of
Chronic Lyme Disease

John E. Edwards, Jr., M.D. (Chair)
LAC Harbor-UCLA Medical Center
Torrance, California

Carl Brenner
Lyme Disease Coalition of New York
Hawley, Pennsylvania

Phyllis Mervine
Lyme Disease Resource Center
Ukiah, California

Justin Radolf, M.D.
Department of Internal Medicine
University of Texas Southwestern Medical Center
Dallas, Texas

Donald H. Gilden, M.D.
Department of Neurology
University of Colorado School of Medicine
Denver, Colorado

Fred A. Gill, M.D.
Bethesda, Maryland

J. Stephen Dumler, M.D.
Department of Pathology
The Johns Hopkins university School of Medicine
Baltimore, Maryland

Lyme Disease Advisory Panel Summary Report
http://www.x-l.net/Lyme/nihsep96.htm

-----
NIH News Release:

FOR IMMEDIATE RELEASE
Friday, June 28, 1996
John Bowersox
(301) 402-1663
Bowersox@nih.gov

NIAID Awards Contract for Post-Lyme Disease Syndrome Studies

The National Institute of Allergy and Infectious Diseases (NIAID) has
awarded a five-year contract to the New England Medical Center (NEMC)
in
Boston, Mass., to study the pathogenesis and treatment of post-Lyme
disease syndrome (PLDS). Mark Klempner, M.D., is the principal
investigator of the $4.2 million study.

"This research will help us answer important questions regarding the
nature of Lyme disease sequelae and the most effective treatment for
individuals affected by this syndrome," says NIAID Director Anthony S.
Fauci, M.D.

Lyme disease is caused by infection with the tick-borne spirochete
Borrelia burgdorferi. Since 1982, when the organism was first
identified
by NIAID scientists, more than 50,000 cases of Lyme disease have been
reported in the United States. Patients usually are treated
successfully
in the early stages of the disease with a two- to four-week course of
oral antibiotics. Additional treatment with intravenous antibiotics may

be required in some cases. Several months after patients with the
initial symptoms of Lyme disease have been treated, some of them
develop
PLDS, a condition also known as chronic Lyme disease and characterized
by persistent musculoskeletal and peripheral nerve pain, fatigue and
memory impairment.

"There is much uncertainty about the pathogenesis of PLDS. We don't
know
if it is caused by ongoing active infection with B. burgdorferi or
another tick-borne pathogen, or if PLDS symptoms result from
reinfection," says John R. La Montagne, Ph.D., director of NIAID's
Division of Microbiology and Infectious Diseases. "Inflammatory or
autoimmune responses occurring during early infection, prior to
treatment with antibiotics, may also play a role in PLDS. We also have
a
lot to learn about its clinical manifestations. This contract will
allow
us to define this syndrome more precisely and develop rational
strategies for treating it."

As contractor, NEMC researchers will work closely with NIAID staff, and

collaborate with scientists at New York Medical College, the University

of Minnesota School of Medicine, and Tufts university School of
Medicine. Studies on the cause or causes of PLDS and the evaluation of
potential therapies for patients with PLDS are planned. Treatment
success will be measured with a variety of tests that assess symptoms,
signs and laboratory manifestations of PLDS.

This contract award to NEMC follows a rigorous objective review
process,
during which all proposals received under an NIAID solicitation were
evaluated and scored by non-government Lyme disease experts. The new
study further expands NIAID's growing portfolio of Lyme disease
research
projects. NIAID currently supports a variety of investigator-initiated
studies of the pathogenesis, diagnosis and treatment of Lyme disease.
In
addition, intramural scientists from NIAID and other institutes at the
National Institutes of Health (NIH) are collaborating on Lyme disease
studies.

According to NIAID's Phillip Baker, Ph.D., the project officer for the
study, the NEMC researchers will work closely with NIH intramural
investigators.

"Although these new studies will not supply all the answers with regard

to the etiology and treatment of PLDS," says Dr. Baker, "they should
provide meaningful information that can help us move toward the
development of effective solutions to this problem."

NIAID, a component of the NIH, conducts and supports research to
prevent, diagnose and treat illnesses such as AIDS and other sexually
transmitted diseases, tuberculosis, asthma and allergies. NIH is an
agency of the U.S. Public Health Service, U.S. Department of Health and

Human Services.

News Release - June 28, 1996
NIAID Awards Contract for Post-Lyme Disease Syndrome Studies, NIAID
http://www.niaid.nih.gov/newsroom/lyme.htm

-----
Clinical Trials in Progress

Chronic Lyme Disease Is It An Ongoing Infection?

NIAIDs Laboratory of Clinical Investigation has begun recruiting
patients for a study of chronic Lyme disease. The goal of this study is

to determine if persistent signs and symptoms of disease, especially
neurologic ones, are due to ongoing active borrelial infection or to
other pathogenic mechanisms. The study is designed to identify
objective
markers that could be used to substantiate and follow the persistence
of
Borrelia burgdorferi infection in people with presumed chronic Lyme
disease and others exposed to the bacterium. The extent of infection
and
the immune system response to it in patients with neuroborreliosis and
other exposed controls will be evaluated. This comprehensive study
should yield a prospective database upon which diagnostic criteria for
chronic Lyme disease can be established and future therapeutic trials
can be designed.

This study is divided in two parts. In the first part, results of
several different evolving tests for B. burgdorferi infection will be
compared between patients with suspected chronic neuroborreliosis
and five different control groups. The control groups include patients
with Lyme arthritis, persons who recovered from Lyme disease after
therapy, asymptomatic persons incidentally found to be seropositive for

B. burgdorferi who have not been treated, patients with multiple
sclerosis, and healthy volunteers. All study participants except for
the
multiple sclerosis patients and healthy volunteers must have documented

positive Lyme serology confirmed by Western blot.

In the second part of the study, patients with clinical suspicion of
chronic neuroborreliosis who have evidence of persistent infection by
polymerase chain reaction, antigen-capture, or other assays will be
offered four weeks of intravenous ceftriaxone therapy. The therapy will

be given on an outpatient basis, ideally under the supervision of the
referring physician. The participants will then return to NIH for
reevaluation at the end of treatment, and 3, 6, and 12 months later.

This study is being developed collaboratively with scientists in
NIAID's
extramural program, in the National Institute of Neurological Diseases
and Stroke, the National Institute of Mental Health, and the National
Institute of Deafness and Other Communication Disorders, and with Lyme
disease experts at institutions such as the State university of New
York
at Stony Brook, the New England Medical Center, and the Mayo Clinic.
Adriana Marques, M.D., is the principal investigator on the project,
and
Brenda Cuccherini, Ph.D, is co-investigator.

For more information, call 1-800-772-5464 x605, or send a
self-addressed
envelope to the following address: NIAID Chronic Lyme Disease Study,
Building 10, Room 11N228, 10 Center Dr., MSC 1888, Bethesda, MD 20892-
1888.

Chronic Lyme Disease Is It An Ongoing Infection?
Clinical Trials in Progress, January 1996
http://www.niaid.nih.gov/publicatio../0696/page6.htm

---------------
News articles on the NIH chronic Lyme disease study:

Subject:  Time Magazine Article 7/28/97
Date:  22 Jul 1997 00:00:00 GMT
From:  "Rita Stanley" <ritastan@worldnet.att.net>
Newsgroups:  sci.med.diseases.lyme

JULY 28, 1997 VOL. 150 NO. 4

HEALTH

TICK, TICK, TICK..
IT'S PRIME TIME FOR LYME DISEASE. PULL UP YOUR SOCKS AND FOLLOW THE
CONTROVERSY

BY CHRISTINE GORMAN

Joseph Dipaoma, 58, of Bedford, N.Y., never saw the pinhead-size tick
that bit him. But there was no mistaking the angry red rash that
blossomed on his forearm. He had Lyme disease, which three weeks on
antibiotics quickly cured. Still, five years later, he sometimes
wonders
if the infection is really gone. "I get a lot of aches and pains," says

the part-time delicatessen worker. "In the back of my mind, there's
this
question: Could it be a residue of the Lyme? Or have I been standing
behind the counter too long?"

Twenty years after the first cases of Lyme disease were reported in and

around Old Lyme, Conn., the epidemic of tick-borne infections seems to
be taking a detour into the twilight zone. Doctors know how to diagnose

it--most of the time. They can even cure it--most of the time.
Pharmaceutical companies are working on two promising vaccines that
could be approved by the U.S. Food and Drug Administration later this
year. Biologists have even come up with some ingenious methods for
controlling the tick population that carries Lyme. But no one is
satisfied, not the victims who complain that their symptoms seem to
persist, not the doctors who are called upon to treat those victims,
not
the scientists who are being asked to solve a medical mystery that no
one has been able to define clearly. There are now so many mixed
messages about exactly what Lyme is and how it should be treated that
many people are left, like DiPaoma, wondering what to believe.

The battle lines are deeply drawn. Taking a page from AIDS activists,
several advocacy and educational groups are insisting that, among other

things, they be consulted in the design of scientific studies of Lyme.
Their input has not been entirely welcomed by the scientific community.

One outspoken program officer at the National Institutes of Health was
so vociferous in his criticism of the Lyme groups that he was barred
from having anything more to do with the disease. His cause was taken
up
three weeks ago in an op-ed piece in the New York Times that criticized

the lay groups and pleaded with them to "let scientists do their job."

A few facts are clear. Lyme disease is caused by one of a group of
corkscrew-shaped bacteria called spirochetes. It is spread when
infected
deer ticks, or other members of the genus Ixodes, bite their potential
hosts, which include field mice, wood rats and suburbanites. Lyme has
become endemic in the Northeastern U.S. It has also been found in
Canada, Europe and Australia. The initial infection is usually
accompanied by an expanding red rash, which generally, but not always,
resembles a bull's-eye. Caught early enough, the Lyme infection can be
completely cleared by taking oral antibiotics.

Things quickly get tricky, however, when you focus on the anomalies.
Sometimes the disease isn't caught soon enough. Sometimes the
spirochetes invade the nervous system, which is beyond the reach of
most
oral medications, in which case they must be flushed out with
antibiotics that are administered intravenously. Everyone agrees that
such complications occur. But some people think they are the exception,

while others believe they are the rule.

The debate gets downright vicious when the subject turns to "chronic
Lyme disease," a catch-all term that means different things to
different
people. Some patient advocates and their medical allies believe the
Lyme
spirochete tends to persist in the body even after standard antibiotic
treatment. This camp generally favors intravenous antibiotic therapy to

treat chronic Lyme. On the other hand, some academic researchers and
their allies argue that people with chronic Lyme fall into one of two
categories: they either have hypersensitive immune systems that have
overreacted to an earlier, no longer viable, Lyme infection--in which
case antibiotics are useless--or they never suffered from Lyme disease
in the first place and are ascribing to Lyme various aches and pains
that actually have nothing to do with the disease.

This difference of opinion has significant implications for treatment.
Intravenous antibiotics can cost tens of thousands of dollars,
especially if hospitalization is required. Moreover, there is a risk
that the catheters used to administer the drugs may become
contaminated,
leading to serious infections of the bloodstream and even the heart.
Clearly, intravenous antibiotics should not be withheld from people who

truly need them. Who truly needs them is, of course, what's in dispute.

The NIH is funding a $4.5 million study in an effort to sort out both
the best definitions and the best treatments for chronic Lyme disease.

Meanwhile, a group of biologists in central Texas may have come up with

at least a partial solution to the Lyme problem. "We call it the four-
poster," says John George, a tick specialist with the U.S. Department
of
Agriculture in Kerrville. It's a bin full of corn surrounded by
specially angled rollers. As deer push in to eat the corn, the rollers
coat the animal's head and neck with a pesticide that targets mites and

ticks. Pilot studies on 50-acre plots have produced a 95% drop in the
local tick population. "What's neat about this is that it's safe for
the
deer and doesn't involve wholesale spraying," George says. "We're
hoping
to try this out very soon in the Northeast." It may not seem very
sophisticated to the folks in Old Lyme, but at least it targets ticks
and not people.

TICK, TICK, TICK.., Time Magazine, 28 Jul 97
http://cgi.pathfinder.com/time/maga..ealth_tick.html
or
http://groups.google.com/groups?hl=..3cf%40default#p

-----
Science, Vol. 270, October 13, 1995, pp 228-229.

NIH GEARS UP TO TEST A HOTLY DISPUTED THEORY
Eliot Marshell

The National Institutes of Health (NIH) is preparing to fund a
$1-million-a-year study that it hopes will settle a dispute that has
riven a segment of the medical community in the past few years.  At
issue: Is there a chronic form of Lyme disease that sometimes persists
after conventional antibiotic treatment, inflicting a variety of
symptoms such as muscle pain, fatigue, and memory loss on its victims?

A group of physicians and patient advocates believes the answer is an
emphatic "yes", and they have been agitating for the medical
establishment to take them seriously.  The upcoming NIH study means
that
their claims  will finally be put to the test.  But many Lyme disease
researchers are skeptical of the need for this project.

The very existence of the trial is testimony to the persistence of
patient advocacy groups.  They have lobbied Congress for many years to
support research into chronic Lyme symptoms, promoting the need for
long-term therapy.  Their tactics have angered leaders such as Allen
Steere of Tufts University, who was the first to identify the U.S. Lyme

syndrome in the 1970s.  The multimillion-dollar trial that NIH is
planning, he says, "would never have been funded" through the "normal
mechanisms" of investigator-initiated research.  But Greg Folkers, a
spokesperson for the National Institute of Allergy and Infectious
Diseases, says, "This trial has been under discussion for several
years"  - well before Congress recommended that NIH study new
antibacterial
strategies.

Steere, Alan Barbour - a microbiologist at the university of Texas,
San
Antonio- and other researchers believe that there's little evidence to
support the notion that there is an epidemic of chronic infection by
Lyme disease.  Most so-called chronic cases, they believe, are not Lyme

disease at all; NIH's study could be a waste of money.  But advocate
groups - particularly the Lyme Disease Foundation (LDF) of Hartford,
Connecticut, which includes physicians who treat patients - argue that
the disease is more elusive, more malignant, and more difficult to
treat
than academic scientists have  acknowledged.  They believe that the
traditional treatment advocated by physicians at leading medical
schools
such as Yale, Tufts, and the university of Connecticut - 2 to 4 weeks
of
oral antibiotics and, in rare cases when the central nervous system is
infected, 4 weeks of intravenous antibiotics - is in many cases
insufficient to wipe out the disease.

Joseph Burrascano Jr., a Long Island physician who specializes in
treating Lyme disease and has served as board member of the LDF, argues

that more aggressive therapy is often needed.  He prescribes month-long

courses of antibiotics for many of his Lyme patients, including
intravenous therapy.  Kenneth Liegner, a physician in Armonk, New York,

has also written that clinicians should expect " a revolution in our
conceptualization of this disease".  Evidence is mounting, Liegner
says,that "subsets of patients" with as-yet-unconfirmed immune system
weaknesses do not benefit from routine therapy and may require
"prolonged antibiotic treatment".

Patient activists have seized on these arguments and are pushing for
studies which they believe will confirm a more radical attack on the
disease than has been recommended by the establishment so far.  One
objective, says patient advocate Kenneth Fordyce, chair of the
governor's Lyme disease advisory committee of New Jersey, is to get
insurance companies to reimburse patients for antibiotic therapy that
lasts longer than the standard 28 days.

Disagreement between the activists and the medical establishment
erupted 3 years ago, when abstracts of a dozen papers submitted by
clinicians to a Lyme disease conference were rejected by the program
committee as lacking in scientific merit.  The papers - most of which
discussed chronic Lyme cases - were reinstated over the objections of
several researchers after patient advocacy groups protested (Science, 5

June 1992, p. 1384).

After failing to convince athe establishment of its scientific views,

LDF took a route that has been well trodden by AIDS and breast cancer
activists:  It mounted a lobbying campaign.  NIH is now accepting
proposals for a trial that will examine whether patients with long-
lasting symptoms are truly infected with Lyme, and whether they benefit

from prolonged antibiotic therapy.

ORIGINS: OLD LYME.  The tussle between the activists and the Lyme
disease establishment stems in large part from inadequate diagnostic
tests and limited understanding of how the culprit organism survives in

humans.  The symptoms of Lyme disease in the United States were first
identified during the 1970s through Steere's studies of children in New

Emgland who were suffering from swollen knees and joints.  Steere
determined that the syndrome - which was heavily focused around Old
Lyme, Connecticut - is a form of arthritis associated with bites from
deer ticks and a strange, bulls- eye rash, erythema migrans.  It soon
became apparent that Lyme syndrome was similar to an infection that had

been described in Europe in the 19th century.  In 1982, biologist Willy

Burgdorfer at NIH's Rocky Mountain lab in Montana nailed the infectious

agent: a spiral-shaped bacterium (a spirochete) of the Borrelia family,

mainly found in a small deer tick, Ixodes scapularis.  In   honor of
the
discoverer, the bacterium was named Borrelia burgdorferi.

Today, Burgdorfer says that the Lyme organism and other spirochetes -
slow-growing but potent organisms responsible for a variety of disease
including syphilis - deserve more attention from researchers.
Syphillis, for example , " has been known for ages.. But with alll our

advanced technology, we are not in a postion to 100% prove that the
manifestations shown by a patient are due to chronic spirochetosis
(ongoing infection) or something else," such as late-appearing damage
from  an infection that may have stopped much earlier.  The same
uncertainties plague the diagnosis and treatment of Lyme disease,
Burgdorfer says.

The weak understanding of the organism's biology is compounded by the
lack of a good diagnostic test.  Blood tests for human Lyme infection
have been unreliable, often yielding false positives, and, some
physicians say, many false negatives.  It was only in October 1994,
Barbour notes, that leaders of public health agencies from around the
United States met in Michigan to establish common standards for testing

and confirming the presence of Lyme infection.

Because it was hard to diagnose cases with certainty, it was also hard

to sort out the effects of different therapies.  The confusion has been

increased by the widening spectrum of symptoms attributed to Lyme
infection.  Initially, Steere focused on clear-cut indicators - the
rash
and swollen joints.  But subtle effects have now been added to the
list,
including injury to the eyes, the heart, the nervous system, and the
brain.

A POLARIZED COMMUNITY.  As the list of possible ill effects grew, so
did the number of patients who felt they were suffering from Lyme
disease.  Their ranks stood at fewer than 1000 in 1982, but, according
to the Centers for Disease Control and Prevention, rose to more than
13,000 in 1994.  To Steere, the increase is a sign that Lyme disease
"has become an overdiagnosed and overtreated illness".  To back up this

contention, Steere conducted a study, published in the Journal of the
American Association  in 1993, in which he reported that 57% of 788
cases referred to the clinicas Lyme disease patients by other
physicians
were not infected  with Borrelia.

Many other academics - such as Durland Fish and Eugene Shapiro of Yale

- agree with Steere that clinical practice has gone overboard. They
believe many physicians are classifying vaguely defined illnesses as
Lyme disease and selecting antibiotic therapy as the most convenient
solution, particularly for prolonged and ill-defined ailments, such as
diffuse pain (fibromyalgia) and fatigue.  One of the major problems in
this field, says Shapiro, "is not Lyme disease itself but the
misdiagnosis of Lyme disease and anxiety about Lyme disease".

At the other pole are physicians who think Steere and his medical
school colleagues ignore the subtlety and persistence of B. burdorferi.

Burrascano, in a 1993 Senate hearing denounced the "conspiracy..of
university-based" scientists who he said were using  their clout to
promote the "outdated" idea that "Lyme is a simple, rare illness that
is..easily cured by 30 days or less of antibiotics".  Burrascano
points
out that the Lyme bacterium is difficult to detect in the blood after
the initial infection even if it has beenn left untreated.  The
aggressive treaters of Lyme disease have long argued that the
spirochete
hides within cells, deep in joints and connective tissue, in the eyes,
and in the relative isolation of the cerebrospinal  nerve system.
These
locations are inaccessible to routine antibiotic therapy, they argue,
and long-term infections require the use of intravenous, potent
antibiotics over many months.

Somewhere in the middle of the Lyme battleground are physicians like
neurologist Patricia Coyle, a clinician at the Health Science Center of

the State university of New York, Stony Brook, who see merit in
Burrascano's arguments but doubt that many patients are afflicted with
chronic infections.   Coyle, who works in a speical clinic at Stony
Brook that sees 1600 Lyme patients a year, says key questions about
Lyme
infection remain unanswered.

First, Coyle asks: "Does the spirochete go into the cells or not?  We
don't know."  However, she says in vitro studies suggest that it does,
and that it may escape antibiotics that way.  Second, Coyle would like
to know to what extent and how often the spirochete penetrates the
central nervous system.  Also, she would like to confirm which
antibiotics are best at attacking it there.  Third, she would like to
learn whether the organism enters a quiescent period after infection.
While scientists have been exploring these issues in laboratory
studies,
Coyle argues that it is important and "very practical" to carry out a
large clinical trial, because it's risky  in dealing with infections to

extrapolate from bench to bedside.

These are just the kinds of questions  that NIH's clinical trial will
address.  The aim is to recruit patients who have previously been
diagnosed and given routine therapy for Lyme disease, but whose
symptoms
persist.  They will be carefully screened to fit criteria - as yet
undefined - of confirmed Lyme patients.  And they will be assigned
blindly to one of several treatment  regimens, including a placebo
group, to be followed for several years, probably at more than one
center.  "One of the big unanswered questions", says John LaMontagne of

the National Institute of Allergy and Infectious Diseases, "is whether
or not Borrelia produces some sort of permanent neurological damage
that
cannot be reversed".

Researchers such as Barbour and Steere are concerned that the trial -
if not well designed - could end up an expensive disappointment.  But
Barbour agrees it may serve a useful purpose.  The debate among
clinicians about what causes long-term symptoms and how to cure them
"needs to be settled", he says.  "People are spending millions of
dollars on antibiotics," hoping to be rid of all kinds of symptoms.
Adds Burgdorfer: "Once we have the answers to these questions, all the
other stuff..the politics..the quarreling among the scientists, will
disappear."  In a community so split, that may be a forlorn hope.

NIH Gears Up To Test a Hotly Disputed Theory, Science, 13 Oct 95
sci.med.diseases.lyme:
Lyme conflict- part of the story-repost Science Article
http://groups.google.com/groups?hl=..0ng35.aol.com#p

---------------
Information on the NIH chronic Lyme disease study posted on the
sci.med.diseases.lyme USENET newsgroup:

Subject:  Opinion - Chronic Lyme Study
Date:  09 Mar 1999 00:00:00 GMT
From:  steve.mclain@dol.net (Steve J. McLain)
Newsgroups:  sci.med.diseases.lyme

I recently attended a review of the NIH Chronic Lyme study.  I'm
posting
information about the enrollment criteria, study criteria and contacts
separately.

In this post I am presenting with the kind permission of the principal
investigator Mark Klempner, M.D., some of the data from the review.
For
those interested in hearing more, Dr. Weinstein will be presenting an
update of the study at the LDF Medical Conference in New York on
Saturday April 10.

I also want to offer some opinions and observations, and hopefully
start
a thread of discussion about the study.

First of all the data:

The majority of the enrolled patients report improvement in their Lyme
symptoms from antibiotic treatments prior to enrollment.  In the
analysis of the first 45 patients enrolled in the study 53% reported
improvement in joint pain (arthralgia), 27% reported improvement in
muscle pain (myalgia) and 42% reported improvement in their energy
level
(fatigue and malaise) during or after prior antibiotic therapy for CLD.
Over 75% reported improvement in one or more symptom with prior
antibiotic treatment.

The western blot test is picking up some seropositive patients who are
negative by ELISA.  Of the 45 patients enrolled, 2 (4.4%) were ELISA
negative and IgG western blot positive.  There were 7 (15.6%) that were
indeterminate by ELISA and positive by IgG western blot.  These tests
use the CDC/Dearborn criteria for the western blot.

New objective tests to distinguish chronic Lyme patients from control
groups are being developed.  Dr. Klempner recently published a paper
reporting that a 130 kilodalton CSF matrix metalloproteinase without
MMP-9 is found in 78% of untreated patients with neuroborreliosis
(confirmed by CSF antibody index > 1.2 or positive PCR).  This pattern
was found in only 6% of control patients and thus may be a useful
marker
for neuroborreliosis.  Now they have found that 64% of patients
enrolled
in the Chronic Lyme study also have 130 kilodalton CSF matrix
metalloproteinase without MMP-9, i.e. the same pattern.  He also
discussed efforts to better characterize chronic Lyme patients by
developing new objective tests based on serum and CSF cytokines.

I was impressed by the scientific breadth of the study and the personal
commitment that Dr. Klempner and Dr. Weinstein have made to recruiting
patients and obtaining a definitive outcome.   I believe that the
principal investigators will reach whatever conclusions the data takes
them too.  I see no evidence of a hidden agenda in this study.

I believe that there is a good chance that this study will demonstrate
that this group of patients is antibiotic responsive.  The enrolled
patients are so impaired on the SF-36 Health survey that even modest
improvement should be detectable, i.e. the study should be very
sensitive.  The majority of enrolled patients report a positive
response
to antibiotics in the past, and the enrollment criteria exclude those
who have been treated longer than 60 days with IV antibiotics.  I think
this exclusion is a good idea because in my opinion these patients are
less likely to show a benefit from the length of treatment given in
this
study.

Some have argued that the enrollment criteria are too strict and
exclude
many patients with Chronic Lyme disease.  This is a personal concern of
mine. I am ill with what I believe to be antibiotic responsive chronic
Lyme disease. I have objective evidence exposure to Lyme disease and
active symptoms, but I do not meet the enrollment criteria.  I've
thought about this issue a lot and discussed it with others more
knowledgeable about study design.  There is a delicate balance in
choosing enrollment criteria that capture patients that one is
reasonably sure were exposed to Lyme disease without excluding the very
group that one is trying to study.  The seronegative group (EM
enrollment criteria) helps in this regard - it has patients with a wide
range of antibody response.  They are only seronegative in the sense of
the overly strict (in my opinion) Dearborn/CDC criteria.  Many have one
or more bands by western blot.

Obviously, enrolling in the study is a very personal decision that
should be done in consultation with your doctor.  I would not encourage
someone with neurological problems that are progressively worsening to
enroll in this study.  In my opinion, patients in that category with
evidence of Lyme disease should seek immediate agressive antibiotic
treatment.  I DO want to encourage people to consider enrolling if they
have persistant symptoms that are relatively stable. I believe that
multiple benefits could come from this study.  We may get conclusive
evidence regarding the antibiotic responsiveness of this group of
patients including whether any current tests are predictive of
responsiveness.  We will undoubtedly learn more about the disease that
will aid in development of better tests and perhaps even treatments.

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PART 6 .med.diseases.lyme: Opinion - Chronic Lyme Study http://groups.google.com/groups?num..n&safe=3Doff&t= h=3D72d79ce701362a6e,30&rnum=3D1&ic=3D1&selm=3D1dof52j.hqpzd217l83ggN%40wil= 69.dol.net ----- Subject: NIH Chronic Lyme Study info Date: 09 Mar 1999 00:00:00 GMT From: steve.mclain@dol.net (Steve J. McLain) Newsgroups: sci.med.diseases.lyme I recently attended a review of the NIH funded clinical study of Chronic Lyme Disease. I am going to post two items to the NG about the study. This post is informational, covering a description of enrollment criteria and the study protocol. For more information and contacts for enrollment see the web site http://www.nymc.edu/lyme/ I will post separately my impressions from the review given by the principal investigator Dr. Klempner, and my opinions about the study. The study is a randomized double-blind placebo-controlled trial of the safety and efficacy of ceftriaxone (Rocephin) and Doxycycline in the treatment of chronic Lyme disease. Additional patients are currently being sought for this study. The principal investigator is Mark S. Klempner, M.D. at Tufts New England Medical Center. The other major study site is New York Medical College, and the program at that site is headed by coinvestigator Arthur Weinstein, MD. For questions concerning details about the study, you can contact Gary Johnson in Boston at (617)-636-4893 or Delona Norton at (914)-594-4530 in Westchester County, NY or e-mail to gary.johnson@es.nemc.org or delona_norton@nymc.edu There are two patient groups in the study and the enrollment criteria are different for the two groups. The MAJOR enrollment criteria are: Seronegative group: A past history of a physician documented erythema migrans (bullseye rash) Must be seronegative by IgG Western Blot (Dearborn criteria) at time of enrollment. Physician documented history of prior antibiotic treatment; however, the patient must not have had oral antibiotics for Lyme disease in the last 7 days or IV ceftriaxone (Rocephin) or cefotaxime (Claforan) treatment for Lyme disease within the last 60 days. Patients who have previously received more than 60 days of IV ceftriaxone (Rocephin) or cefotaxime (Claforan) treatment for Lyme disease are excluded from the study. A history of one or more symptoms of Lyme disease (from a list of 4 symptoms) One or more symptoms of Lyme disease that have persisted for at least 6 months (from a list of 3 symptoms). Patients with symptom history of greater than 12 years are excluded. Seropositive group: Similar criteria to the seronegative group except that a history of erythema migrans is NOT required, and patients are required to be IgG positive by Western blot (Dearborn criteria) at the time of enrollment --- All patients who have positive PCR Borrelia DNA in blood or cerebrospinal fluid at the time of initial evaluation will be excluded and referred to the intramural NIH study on Lyme disease. Summary of protocol: Enrolled patients will get a multitude of laboratory tests. A lumbar puncture (spinal tap) will be preformed to obtain spinal fluid for some of these tests. Patients will have neuropsychological testing and will fill out the SF-36 Health survey. Half of the patients will receive IV ceftriaxone (Rocephin) 2 grams/day for 30 days followed by 60 days of Doxycycline (200 mg/day). The other half of the patients (placebo group) will receive IV treatment with a dilute solution of vitamins for 30 days followed by 60 days of placebo oral medication (dextrose). Lab tests will be done periodically during treatment, and major evaluations by one of the principal investigators will be done at 30 days (end of IV), 90 days (completion of oral therapy), 180 days and 360 days. In those patients whose initial spinal fluid is abnormal for any baseline parameters, there will be a follow-up lumbar puncture at 90 days. The primary outcome for this study is defined as an improvement in the patients' health related quality of life as determined by the SF-36 Health survey. In other words the primary means to evaluate the efficacy of this antibiotic therapy will be the patients' self-reporting of physical and mental well being via the SF-36 Health survey. sci.med.diseases.lyme: NIH Chronic Lyme Study info http://groups.google.com/groups?num..n&safe=3Doff&t= h=3Dae3d2e86a45ff78e,54&rnum=3D1&ic=3D1&selm=3D1dof4xk.1w3bfmu10pip48N%40wi= l69.dol.net ----- Subject: Klempner's talk in Westchester Date: 16 May 1998 00:00:00 GMT From: cramoy@aol.com (Cramoy) Newsgroups: sci.med.diseases.lyme For those of you who couldn't be there, here is a summary. Carolyn Dr. Mark S. Klempner Addresses Westchester Lyme Support Group Mark S. Klempner, M.D. spoke at the regular monthly meeting of the Westchester Lyme Disease Support Group in White Plains, NY on May 12th, 1998. Dr. Klempner=92s purpose in addressing the group was to thoroughly explain, and hopefully recruit patient volunteers for, the NIH sponsored studies of chronic Lyme disease which he heads as the principal investigator. His co-investigators are Arthur Weinstein, M. D., Linden Hu, M. D., Allen C. Steere, M. D., and Gary Wormser, M. D. Dr. Klempner is having to put tremendous effort into the recruitment of volunteers because the design of the study has raised many concerns among the Lyme patient community. Furthermore, past actions by certain of the investigators have led to tremendous anger and distrust by many chronic Lyme patients and the doctors who treat them. Although the investigators are certainly world-renown in Lyme disease research, they all are known to have put great effort into convincing the medical community that Lyme disease is seldom chronic and that many patients and doctors are wrong in claiming that the chronic Lyme that does exist is usually the result of persistent bacterial infection by the Borrelia burgdorferi spirochete. This group has long opposed =93long-term=94 antibiotic therapy and has consistently stated that no more than 2 to 4 weeks of antibiotics are needed to cure Lyme disease. Dr. Klempner finds himself in the position of trying to recruit chronic Lyme patients who may, in the past, have been told by members of this investigative team that they did not have Lyme at all, but were depressed, hypochondriacal, or had chronic fatigue syndrome, fibromyalgia, or post-Lyme syndrome. Many patients, patient advocates and medical professionals have come to question the intellectual honesty of some of these researchers. It seems ironic that this same group is now looking for the cooperation of patients they severely alienated when the original pleas for medical help with this devastating disease were made. Many patients feel that the design of the study is skewed in such a way that it cannot prove what it claims it has set out to prove. They don=92t agree with the definition of =93long-term antibiotic therapy=94. They believe that the dose of oral doxycycline to be given is inadequate. They feel that patients will be reluctant to volunteer because of the possibility of being placed in the placebo group. And they fear that the treatment period is insufficient to bring about significant improvement in the symptoms of patients who have been infected for an extended period, thereby leading to incorrect research conclusions that could further divide the two sides of the Lyme disease controversy. If anyone can pull off this task of recruiting the necessary volunteers from an admittedly wary group, it will be Dr. Klempner. He is a personable, cheerful and obviously knowledgeable presenter. He gave a very clear, concise presentation of the study design and goals, and then fielded all questions politely and respectfully. He joked easily with the group and spoke often of his three teen-age children. He showed no signs of impatience, even when questions went off-track, or when negative concerns were expressed. He communicated a sincere desire to help and to understand. The study is designed to answer five major questions: 1=2E Does intensive antibiotic treatment benefit patients with post-treatment chronic Lyme disease (Lyme disease which has remained or returned despite previous antibiotic therapy)? 2=2E Is there evidence of persistent infection in post-treatment chronic Lyme disease? 3=2E Is there evidence of co-infection in post-treatment chronic Lyme disease? 4=2E Is there a better diagnostic test for Lyme disease? 5=2E Do specific parameters predict who will get better on intensive antibiotic treatment and who will not? There will be a seropositive and a seronegative group in the study. Those in the seropositive group must meet the following criteria: 1=2E Positive IgG western blot by the Dearborn criteria 2=2E Over 18 3=2E Be able to give informed consent 4=2E Have been previously treated for Lyme disease 5=2E Have a history of exposure or some manifestations of acute disease documented in the past. 6=2E Be currently suffering with symptoms such as musculoskeletal pain, fatigue, neuropathy or radicular pain 7=2E Symptoms of no more than 12 years duration. Those in the seronegative group must meet criteria #2 through 7 above and have had an erythema migrans rash that was documented by a medical professional. Patients will be repeatedly and extensively evaluated via blood tests, urine tests, written assessments and psychological testing. Areas looked at will include health related quality of life, depression, and mental functioning. Klempner feels that the assessment tool they are using to measure quality of life (the SF-36 questionnaire which is derived from the Medical Outcomes Study questionnaire) will be able to accurately document improvements in the patients=92 overall health. The determination of who is =93better=94 will be made at the six month point. Follow-up will continue for one year. So far 20 people have been enrolled in the study as post-treatment chronic Lyme patients. These patients have been randomly assigned to an antibiotic therapy group or a placebo group. Those in the antibiotic group receive 30 day of intravenous ceftriaxone (2 grams once a day) followed by 60 days of oral doxycycline (100 mg. twice a day). Also 88 people enrolled as controls have already undergone certain tests. While there are, as yet, no results regarding the efficacy of antibiotic treatment, Klempner had some exciting things to report. (These findings were reported in detail in the Jan-Mar, =9198 edition of the Lyme Times). Already the study has shown that chronic Lyme patients, on average, have more severe health related disability than patients with congestive heart failure or severe osteoarthritis. Additionally there has been confirmation that a metalloproteinase which breaks down collagen (130 kda gelatinase) has been found in the cerebrospinal fluid of 86% of the chronic Lyme patients and appears to be an excellent marker, specific for Lyme disease. The study is designed to include 100 chronic Lyme patients. The total cost of the study will be $4.2 million over a period of up to five years. The antibiotics for the study have been donated by their manufacturers. If the study shows that long term antibiotic therapy =93works=94 (a term that was not defined by Dr. Klempner), the placebo group will then be given the same therapy free of charge. NIH has agreed to a symptomatic study as a follow-up if the antibiotic therapy is not shown to =93work=94. There is also a parallel study taking place with monkeys. This study is designed to mimic the therapy given to patients and will allow for in depth histological and microbiological studies. During the question and answer period, concern was expressed about what would happen if patients became ill after the 3 month treatment period. Dr. Klempner said that participants would be free to seek treatment outside the study during the follow-up period. Two members of the audience asked about people who had applied but not been accepted in the study. Dr. Klempner said that reasons for exclusion included conditions that would interfere with the ability to assess symptoms (for example, the use of prescription pain medications), and conditions that would make a person susceptible to infection via the IV catheters, such as immunodeficiencies or prednisone therapy. Dr. Cameron expressed concern about adequate assessment of depression and other known psychological and neurological symptoms of Lyme. Dr. Klempner assured him that no fewer than seven assessment tools were being used to measure these factors. Someone else wondered whether the severely ill were excluded from the study by virtue of being unable to get to the testing centers. She was told that almost all evaluation and sample gathering is taking place =93in home=94. Obviously, a trip to the testing center will be necessary for spinal taps to be performed. In response to a question about preventing Lyme disease, Klempner emphasized the importance of regular tick checks. He said that in cases where a tick from an endemic area had been attached for more than 24 hours, he would treat immediately with antibiotics. After the presentation, most people agreed that Dr. Klempner had done an excellent job of explaining the study and had cleared up many questions. However, fear and doubt still were strong. Many feared that this study will just set another =93magic number=94 for antibiotic therapy which will be used to deny insurance coverage and to prove the mental instability of patients who insist that their symptoms persist, and the incompetence of doctors who prescribe longer-term therapy. Everyone is hopeful that this study will help to bring the two sides of the Lyme debate closer together and that a constructive dialog will result. However, despite Dr. Klempner=92s charm and obvious desire to sort out some of the puzzles of chronic Lyme, few believe that his colleagues have any desire to do any more than prove that they have been right all along. sci.med.diseases.lyme: Klempner's talk in Westchester http://groups.google.com/groups?hl=..Doff&ic=3D1&th= =3Df8257dbe41c09c77,6&seekm=3D1998051604105400.AAA12748%40ladder01.news.aol= .com#p

PART 7 Carl Gives Us a Little Update: Subject: Update on NIH Chronic Lyme Study (fairly long) Date: 12 Feb 1997 00:00:00 GMT From: cbrenner@postoffice.ptd.net (carl brenner) Newsgroups: sci.med.diseases.lyme I thought people in the newsgroup might be interested in a little progress report on the NIH Chronic Lyme study. Things are moving slowly, but they're moving. Here is where everything stands now. Some of the following text (parts of items 5 and 6) has been taken from a summary prepared by Phil Baker, the Program Officer for Lyme disease at NIAID. First, the old news: 1) NIAID is conducting an intramural study on chronic Lyme disease. The emphasis is on neuroborreliosis. The aim of this study is to try to find a combination of clinical markers or laboratory values that are specific to chronic borreliosis, in order to aid in future diagnosis, and to follow the clinical course of patients after treatment for neurologic Lyme disease. A summary of the study objectives has been posted in this newsgroup on several previous occasions; interested readers can recover these posts from the DejaNews web page [see the sci.med.diseases.lyme USENET newsgroup archives at Google.com]. Briefly, patients with neurologic infection will be rigorously tested and compared with various control groups, such as Lyme arthritis patients, MS patients, recovered patients, asymptomatic seropositive individuals and a group of healthy volunteers. Patients in these control groups will undergo similar testing. The testing regime is extremely comprehensive, and includes a complete blood workup (B. burgdorferi ELISA and Western blot, CBC, sedimentation rate, ANA, serum creatinine, blood urea nitrogen, alkaline phosphatase, SGOT, SGPT, GGPT, total bilirubin, LDH, CPK electrolytes, albumin, fasting glucose, TSH, rheumatoid factor, etc.), urinalysis, babesia and ehrlichia screening, HIV, HTLV and syphilis tests, neurologic exam, neuropsych workup, EKG, chest X-ray, brain MRI, nerve conduction studies (if appropriate), HLA typing, blood lymphocyte phenotyping, blood cytokine profiles, blood culture and PCR for Borrelia burgdorferi, and lumbar puncture. CSF will be examined for borrelial antigens, DNA and immune complexes, as well as routine CSF parameters (other bacterial, fungal and viral cultures, cell counts, oligoclonal bands, total IgG, etc.). Patients with chronic active neuroborreliosis will be offered treatment through their primary care physician, and will be evaluated at NIH at periodic intervals thereafter. These studies are presently underway, although patient enrollment has unfortunately been quite slow so far. 2) An extramural study of chronic Lyme disease will also be undertaken. The contract to conduct these studies was awarded to a group of researchers at Tufts/New England Medical Center (hereafter referred to as NEMC). Investigators from New York Medical college will also have a prominent role. The study population will be drawn from both sites. This award was protested by the State university of New York at Stony Brook, which had competed for the contract. The protest was denied by the Government Accounting Office on December 5, 1996. A copy of the GAO's decision and rationale can be found on the GAO home page (http://www.gao.gov/decisions/bidpro/274269.htm); this document also has been previously posted to the newsgroup. 3) The proposed extramural study protocol was presented by Mark Klempner, the study's principal investigator, to the Advisory Committee for Studies on Chronic Lyme Disease at a meeting at NIH last August. (A description of this initial protocol has also appeared in this newsgroup on several occasions.) The Advisory Committee was assembled by NIAID to help oversee the carrying out of the extramural study. (Because the award is in the form of a contract, rather than a grant, a greater degree of supervision is implied.) There are at present seven members on the panel; Phyllis Mervine and I are the two patient representatives. OK, now some newer stuff: 4) An abridged version of the Advisory Committee's first report, dated September 4, 1996, is now available through the NIAID home page at http://www.niaid.nih.gov/dmid/lyme.htm. Unfortunately, little context for the report is provided -- in other words, without copies of the proposed protocol, readers may not understand all of the panel's comments. The reason that no protocol is posted is that the final study design has yet to be approved by the various bureaucracies that need to approve it. (More on this later.) Rather than post a protocol that will likely change, NIH is electing, understandably, to hold off until the protocols are final, or nearly so. It is hoped that a summary of some of the basic elements of the protocol will be available on the NIAID page fairly soon. I'm sorry that I can't be more specific -- I just have no idea when it will be ready. Neither Phyllis nor I has yet seen the modified protocols in writing. One thing we can say for sure is that the protocols now contain a number of elements that were not in the initial study design. For example, skin biopsies from patients will be examined for the presence of borrelial DNA, and urine will be tested for the presence of borrelial antigens at frequent time intervals. This should provide important information on patients' infective state and on the effect of antibiotic therapy on persistence of infection. 5)The Data Safety and Monitoring Board (DSMB) for the extramural studies has been formed. It consists of 5 members -- two infectious disease specialists, one ethicist, one psychiatrist and one biostatistician. The DSMB is charged with the responsibility of monitoring the safety of patients in clinical trials such as this. At periodic intervals during the course of a trial, the DSMB examines the accumulated data on safety and, if appropriate, efficacy, in order to make recommendations concerning continuation, termination, or other modifications of the trial based on the observed beneficial or adverse effects of the treatments being tested. "Stopping rules" are defined in advance of data analysis. For example, if patients receiving antibiotics in this study are responding overwhelmingly better than those getting placebo, this panel will step in and terminate the administration of placebo to future patients. (Remember, the investigators distributing the medications to patients will be blinded -- that is, they will not know which patients are receiving antibiotics and which are receiving placebo, so they will be unable to detect even the most dramatic, "obvious" trends.) 6) OK, here's the hardcore bureaucratic stuff: the modified protocols and consent forms have been reviewed and approved by the Human Investigation Review Committee at NEMC. However, these probably will not turn out to be the exact, final protocols. The protocols and consent forms approved by the Institutional Review Board (IRB) are now in the process of being reviewed internally by NIAID Department of Microbiology and Infectious Diseases (DMID) program staff and the DMID has begun discussions with the Food and Drug Administration (FDA) concerning an Investigational New Drug (IND) application. This may (and probably will) require further refinements in the protocols and consent forms which, in turn, would have to be approved once more by the IRB at NEMC. This feedback loop continues until everybody gets sick of it and throws up their hands. At that point, the study will begin. 7) Once the protocols are final, or nearly so, and if people are interested, I would like to hold a meeting, probably in Westchester County, to brief patients and other interested parties on the proposed study design. This will be an opportunity for people to ask questions and for all of us to exchange ideas and thoughts on the study and, if there is enough interest, to discuss future directions for research. NIH is very interested in and quite responsive to patient thoughts on potential research directions. For patients who are unable to attend the meeting because of geography or illness, a transcript of the proceedings will be available. I apologize for the lack of hard information about the protocols, but hope and expect to have more details for you soon. Please be aware that I'll be away (and probably offline) for the next week or so and will be temporarily unable to respond to email or posted followup queries. Carl Brenner

PART 9 FINAL PART from this Source: Other resources regarding the NIH chronic Lyme disease study: LymeNet Newsletters: Vol#6 #09 III. LYMENET: Patient Describes Positive NIH Intramural Study Experience http://www2.lymenet.org/domino/nl.nsf/UID/6-09 Vol#6 #05 I. LDRC: Chronic Lyme study patients showing extraordinary debility II. LDRC: NIH looking for more patients for chronic neuroborreliosis study http://www2.lymenet.org/domino/nl.nsf/UID/6-05 Vol#4 #11 II. NIAID: NIAID Awards Contract for Post-Lyme Disease Syndrome Studies III. NIAID: Questions and Answers About NIAID's Chronic Lyme Disease Study http://www2.lymenet.org/domino/nl.nsf/UID/4-11 ----- Other studies: The NIH monkey study: Animal Models in Chronic Lyme Disease Contact: Dr. Philip Baker Lyme Disease Program Officer Bacteriology and Mycology Branch Telephone: (301) 496-7728 Internet: pb26o@nih.gov Description of Project: To solicit proposals on the use of appropriate animal models, having neurologic abnormalities generally associated with chronic Lyme borreliosis, to characterize the mechanisms involved in the pathogenesis of chronic neuroborreliosis, as well as to develop novel and effective approaches to detect, monitor, and treat persistent borrelial infections of the central and peripheral nervous system. Objective: To supplement ongoing research on: [a] the pathogenesis of Lyme borreliosis; and [b] mechanisms involved in the expression of neurological symptoms characteristic of chronic Lyme borreliosis. The information derived from such studies ultimately will be used to devise rational and more effective clinical approaches for the treatment of chronic Lyme borreliosis in humans, as well as to assist in the interpretation of the results obtained in ongoing studies on the efficacy of antibiotic therapy for the treatment of chronic Lyme borreliosis. NIAID Council News - DMID Concepts September 1997 http://www.niaid.nih.gov/ncn/conmid-s.htm#AMCLD --------------- See also: Lyme Disease in the United States and Canada http://www.geocities.com/HotSprings/Spa/6772/lyme.html --------------- Prepared by Art Doherty Lompoc, California doherty@utech.net

>From the LymeNUT Newsletter (now defunct it used to be a valuable resource, in fact Lymenet used to have lots of good stuff, including a database of medical abstracts, current news articles, an online library--unfortunately notwithstanding the thousands of dollars they raise ever year and the fact that they are now OWNED by lda new jersey, the only thing ever updated is the FLASH board, everything else they stopped updating five or more years ago for some inexplicable reason): http://www2.lymenet.org/domino/nl.nsf/UID/4-11 III. NIAID: Questions and Answers About NIAID's Chronic Lyme Disease Study --------------------------------------------------------------------- Sender: Judy Murphy <JMURPHY@flash.niaid.nih.gov> Office of Communications National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 20892 June 1996 The National Institute of Allergy and Infectious Diseases (NIAID) recently announced the award of a five-year contract to the New England Medical Center (NEMC) to study the pathogenesis and treatment of post-Lyme disease syndrome (PLDS). Many people have called NIAID to ask questions about this contract and to voice their opinions. The question-and-answer document below is designed to respond to these concerns to the extent possible at this time. It is important to keep in mind that this is a research study, designed to help scientists better understand Lyme disease and to develop better ways of treating this disease. The research carried out under NIAID's direction as a part of this contract will increase our knowledge of this disease and provide the foundation for new and potentially more effective approaches to be explored in future studies. The ultimate goal will be to improve the diagnosis and treatment of people with PLDS. Q. Why is NIAID funding this study? A. Although scientists have identified Borrelia burgdorferi as the bacterium that causes Lyme disease, we need to know much more about the pathology associated with this disease. Scientists have many questions about the chronic manifestations of Lyme disease. The issue is not whether such a syndrome exists; rather, it is how B. burgdorferi is able to elicit such a broad range of long-term problems in some people. We don't know whether the symptoms associated with PLDS are caused by one or more of the following: an ongoing (persistent) infection with B. burgdorferi or another tick-borne pathogen; reinfection with B. burgdorferi; an autoimmune or inflammatory response associated with the initial infection; or some other yet-to-be- defined mechanism. For this reason, NIAID is using the term PLDS, rather than chronic Lyme disease. The latter implies that the symptoms observed are the result of persistent infection by B. burgdorferi. Although that indeed may be the case, in most instances direct evidence of persistent infection is lacking. We also need to document what constitutes PLDS because the clinical characteristics of this syndrome have not been described precisely. In addition, physicians are uncertain about which treatment strategies would be most effective. For example: * What types of antibiotics should be used? * How long should they be taken? * If beneficial effects occur, how long do they last? * Should drugs other than antibiotics be tested? * What outcomes can be used to determine that a given course of antibiotic treatment is indeed effective? Research under this contract will examine many of these questions in a step-wise and systematic manner. This will involve conducting preliminary studies to more fully characterize PLDS. The study will determine the therapeutic approaches, outcomes and monitoring techniques likely to give the most useful information and help doctors who are treating people with PLDS. Q. Who are the investigators working on this contract? A. Dr. Mark Klempner of the New England Medical Center is the principal investigator. Together with the NIAID project officer, Dr. Klempner is responsible for the overall design and conduct of the studies performed under the contract. Dr. Arthur Weinstein will coordinate all aspects of the study at Westchester County Medical Center/New York Medical College. Dr. Gary Wormser, also at New York Medical College, will oversee the administration of study medications. In this role, he will work closely with the nursing staff to minimize any adverse reactions to antibiotics, as well as bacterial infections sometimes associated with prolonged intravenous therapy. He also will be responsible for the culture of spinal fluid samples to detect the presence of viable B. burgdorferi. Dr. Jesse Goodman, university of Minnesota School of Medicine, will conduct all laboratory tests for the detection of possible co-infecting agents (ehrlichia and babesia). Dr. Allen Steere of Tufts university will oversee blinded serologic assays on patient blood samples. All of these investigators are experts in their fields. Because the studies will be blinded (see below), any possible bias of investigators will be avoided. Q. How were the contract proposals reviewed and evaluated? A. A panel of scientists reviews and evaluates contract proposals, ranking them according to scientific merit, which is one of the chief factors considered in a contract award. Other factors include the projected cost of carrying out the work required by the contract. The contract proposal provides evidence that the investigators can meet the scientific objectives established by the Institute for carrying out the type of studies to be done under the contract. Thus, the proposal provides a means for the review panel to evaluate both the scientific expertise and the soundness of the experimental design devised by the offerors. Although the sample protocol may contain elements that are eventually adopted into the final protocol, its primary purpose is to provide a means for the scientific reviewers to assess the capability and approach of the offerors. In contrast to staff involvement with investigators given a research grant, the Institute staff work with investigators under contract at every step to refine the design of the treatment protocol to ensure that the studies to be performed will achieve NIAID's ultimate objectives. Q. Will clinical trials be part of this contract? A. Yes. Phase III clinical studies are a major component. These will be multicentered studies conducted in collaboration with scientists in the intramural research program of the NIAID and elsewhere. The goal of the studies is to further characterize PLDS so that rational and more effective therapeutic approaches can be devised for use in larger populations of patients. These studies will be double-blind and placebo-controlled. This means that all specimens to be tested will be coded so that neither the investigators nor the patients will know who is getting antibiotic and who is receiving placebo. Only after the study has been completed and all specimens have been analyzed will the codes be broken so that the effectiveness of treatment can be evaluated. Such an approach is designed to ensure objectivity and rule out any possible influence of bias or preconceived ideas about any aspect of the studies. Protocol details still being worked out include: * the antibiotics to be tested -- which ones, in what sequence and for how long; * numbers of patients, which will be determined by the protocol design and biostatistical considerations. Q. Who will oversee the work done under this contract? A. The NIAID Project Officer will have final approval of all studies that will be undertaken. As with all Phase III clinical studies, an independent Data and Safety Monitoring Board (DSMB) -- appointed by the National Institutes of Health (NIH) -- will regularly evaluate the results obtained. In addition, NIAID is establishing an advisory body made up of research scientists, medical experts and members of Lyme disease patient advocacy groups to assist in defining the issues to be addressed and in resolving any problems that may arise during the course of these studies. Q. How will studies conducted under this contract relate to the NIH intramural clinical trial? A. NEMC researchers will work closely with NIH intramural investigators, although the patient populations selected for each study will differ. In the contract studies, patients will have had a documented case of acute Lyme disease, will have received treatment and recovered, but they will subsequently have developed all of the signs and symptoms associated with PLDS. By contrast, patients to be enrolled in the intramural studies will have a higher probability of being actively infected based on the results of a variety of laboratory tests. Although the contract studies will have a placebo arm, all patients enrolled in the intramural studies who fill certain criteria specified in the protocol will receive antibiotic. Investigators in both studies will collaborate to determine whether the immunologic and diagnostic assays used to monitor the effectiveness of antibiotic therapy prove useful for both groups of patients. New assays not currently available to physicians will be used, and NIAID staff hope that these tests will provide valuable insights into PLDS and will prove useful in evaluating the effectiveness of antibiotic treatment. Q. The intramural studies require a positive antibody test and Western blot. Will the contract studies also require such tests, even though some people with symptoms of PLDS are seronegative? A. These antibody tests are used in the initial diagnosis of acute Lyme disease. Although the patients in the intramural studies must have positive ELISA and Western blot tests, the contract study patients may or may not be antibody positive if they have been treated in the past with antibiotics. Q. When will final details of any protocols be complete? A. We plan to be enrolling and treating patients with PLDS by early fall. The intramural study is already open to accrual. As soon as information about the studies becomes available, NIAID will post it on our home page on the World Wide Web (www.niaid.nih.gov) and alert the newsletters on our mailing list. NEMC will also publicize new developments. http://www2.lymenet.org/domino/nl.nsf/UID/6-05 QUOTE OF THE WEEK: "These [chronic lyme] patients are in a condition worse than patients with marked congestive heart failure. They are two and a half standard deviations from normal - among the most deviant of any chronic illness." -- Mark S. Klempner, MD, NIH Extramural Chronic Lyme Study Principal Investigator =====*===== I. LDRC: Chronic Lyme study patients showing extraordinary debility ---------------------------------------------------------------------- This article originally appeared in the January - March 1998 Issue of the Lyme Times Six months into the extramural arm of the NIH funded chronic Lyme disease study, the research team is making wonderful progress, according to principal investigator Mark S. Klempner, MD, of the New England Medical Center (NEMC) in Boston. While no conclusions are possible this early, they are receiving some very strong impressions from the patients they are seeing. Klempner shared some of those impressions in an interview with the Lyme Times. The study has five basic goals: to determine whether a specific treatment regimen benefits patients with chronic Lyme disease; to identify, if possible, evidence of ongoing infection; to investigate the possibility of coinfection; to find new diagnostic tests; and to determine whether there are specific markers which predict who will, and who will not, respond to the treatment regimen. Most remarkable, according to Klempner, is the extraordinary degree of debility they are seeing in this group of patients. Prior to this study, no one had profiled what chronic Lyme disease patients really complain about. The term "vague complaints" has been widely used as a pejorative to trivialize the patients' symptoms. Now, using a well established and professionally respected scale which measures health related quality of life, the NEMC doctors are discovering that patients do indeed experience striking limitations from chronic pain. "Their complaints are not 'vague,'"states Klempner, "but, on the contrary, are very quantifiable. These patients are in a condition worse than patients with marked congestive heart failure. They are two and a half standard deviations [a statistical term] from normal - among the most deviant of any chronic illness." He feels that this finding will remain important, even if other parts of the study are not as definitive. He expressed his confidence in the outcome measures the team has selected and expects to be able to detect any improvement over the course of treatment. Klempner took issue with the popular perception that Lyme disease patients are basically suffering from depression. From his early observations on the approximately 20 patients who have enrolled in the study so far, patients with chronic Lyme disease are not depressed. Their debility is not mental but physical. "They are absolutely normal mentally," he asserted. "What we see so clearly is the significant impact of their bodily pain. This has not been appreciated." An area of particular interest to Klempner is the search for better identifiers which will enable them to differentiate between patients who develop chronic disease and those who don't. He and his colleagues published the results of an earlier study in the February, 1998 issue of the Journal of Infectious Diseases detailing their search for matrix metalloprotease in the cerebrospinal fluid (CSF) of patients with acute neuroborreliosis (e.g. meningitis, facial palsy, positive PCR, culture). This protease is one of a group of enzymes which dissolves the extracellular matrix between cells in normal body tissues. Significantly, the researchers found a 78% incidence of the novel protease in the CSF of neuroborreliosis patients, compared with 6% in the general population or in patients with other neurologic diseases. "We are now looking for this enzyme in patients in the chronic Lyme disease study," explained Klempner. "Of the first 15 patients we tested, 14 have it." The study is on track with over twenty patients enrolled so far, and 60 more are being screened. They hope and expect to enroll a total of 70-80 patients in the first year. Patients are being enrolled both in Boston at New England Medical Center and in the New York area at New York Medical college in Westchester, NY (see box below). After the screening process, they are randomly assigned to a treatment group where they receive one month of intravenous antibiotics followed by two months of oral antibiotics, or to a placebo group. Neither doctors nor patients know which treatment is being given - this is known as a "double- blind, placebo-controlled" study. The codes will be broken after the trial is completed and then the data will be analyzed. Klempner is busy giving talks to explain the study and recruit patients. He is clearly impressed by the spirit of the people who are signing up even though they may only be getting months of a placebo. Over 450 of these chronically ill, debilitated patients have contacted the medical centers for information about the study. "No one is complaining about the treatment protocol, and only one patient has refused the spinal tap. People are really eager to help us and to help their community," he said. For information about the study contact Dr. Mark Klempner or Dr. Linden Hu at 1-888-LYME CTR (1-888-596-3287). New York residents may call the Lyme Research Office at New York Medical College, 914-594-4530. Study Description: http://www.niaid.nih.gov/recruit/phsiiip.htm =====*===== II. LDRC: NIH looking for more patients for chronic neuroborreliosis study ----------------------------------------------------- This article originally appeared in the January - March 1998 Issue of the Lyme Times The intramural arm of the NIH study on chronic Lyme disease is studying chronic neuroborreliosis, or Lyme disease of the central nervous system. They want to find out whether persistent signs and symptoms, especially neurologic ones, are due to ongoing active borrelial infection or other pathogenic mechanisms. According to principal investigator Adrianna Marques, MD, over 600 patients have requested information, but only 20% (120) have returned the paperwork. Of these, 71% were disqualified because they lacked serological confirmation of infection, or in some other way did not meet the eligibility criteria. Altogether, 28 people have been enrolled in the study so far, mostly from the northeast, and two from Florida. Patients who pass the initial screening must come to the NIH Clinical Center in Bethesda, Maryland, for an evaluation which includes a full clinical and neurological examination, routine laboratory tests, EIA or ELISA testing (with confirmatory immunoblot), Babesia and Ehrlichia screening, lumbar puncture, high-resolution MRI, audiologic evaluation, neuropsychological testing and leukapheresis for extensive immune system studies. The tests take approximately four days. All costs of the study and medical care at the NIH and travel to and from Bethesda are covered by the NIH. Marques says the patients are very interesting, although it's too early to see the bigger picture. "Each patient is different," she said. "We are just beginning to get an impression of the group." She performs the physical examination on each one before sending them to specialists for all the other tests. Patients are investigated for hearing abnormalities, and their T-cell responses are examined. Some patients present with a disease like multiple sclerosis; others have fibromyalgia or chronic arthritis. Marques wants to look more closely at how the patients respond to therapy and how their immune systems are functioning, to see if she can figure out a pattern. More patients are needed. To enroll, patients must: * Be seropositive for Lyme infection - that is, have a documented positive Lyme serology test, confirmed with Western Blot. * Have neurological symptoms of at least three month's duration. * Have no other disease that can explain the symptoms. * Be without antibiotic therapy for one month prior to the study. Patients who have evidence of persistent infection by PCR, antigen- capture assay or other assays will be offered four weeks of intravenous ceftriaxone therapy. The therapy will be given on an out-patient basis, ideally under the supervision of each referring physician. The subjects will then return to NIH for reevaluation at the end of treatment, three, six, and twelve months after therapy. NIH is also recruiting people for the control group. They are looking for men and women aged 18 to 65 in the following categories: * People diagnosed with Lyme arthritis, who have continuous joint swelling for more then three months with no other documented cause; * People who have had Lyme disease, according to the CDC Lyme Disease National Surveillance Case Definition, received accepted antibiotic treatment for Lyme disease, and are currently asymptomatic; * People who are seropositive for Lyme infection but are asymptomatic, recall no episodes of disease compatible with Lyme infection, and have not received antibiotic therapy for Lyme disease. People who have serious pre-existing or concurrent chronic medical or psychiatric illnesses are excluded from the study. "Research is a two-way road," said Marques. "It is important to think we are all partners in research. The patients make a big difference. It's their participation that makes it happen." If you are interested in more detailed information about this study, please send a self-addressed envelope to the following address: NIAID Chronic Lyme Disease Study Adriana Marques Building 10 Room 11C405 9000 Rockville Pike Bethesda MD 20892 Study Description: http://www.niaid.nih.gov/recruit/lyme.htm =====*===== http://www2.lymenet.org/domino/nl.n..19?OpenDocument III. LYMENET: Patient Describes Positive NIH Intramural Study Experience -------------------------------------------------------------- Sender: Lindell Lee McElfresh <LindellLee@aol.com> Regarding the National Institutes of Health Lyme Study # 96-I-0052 For five days, beginning August 23rd, I could be found at the NIH campus in Bethesda MD. You would have found me in a better state of mind than had been possible in a long while. Applying to take part in this study is the best thing I have done since the tick bit me. Here are my impressions of the experience. The support staff: Starting with the help I got over the phone while a applying, the shuttle driver that collected me at the airport, the ladies that registered me, the patient representative, the social worker, the food service people, the librarian, the escorts that got me where I needed to be, right through to the travel agent who arranged my trip home, I was treated with politeness at worst and cheerful helpfulness more times than not. This was a far cry from the bureaucratic malaise I was prepared to find at such a large institution. The food, selection and quality, was surprisingly good as well. The doctors and technicians: All the doctors and technicians who looked after, tested, poked, prodded, x-rayed, and scanned me were wonderful. Not once was I confronted with indifference much less arrogance. The nursing staff: Each nurse was kind, friendly and caring. When a shift changed and I was disappointed at not seeing the nurse who had been so nice yesterday, it wasn't long before the new nurse would win me over with a smile and some care and attention. It seems as if a helpful attitude and friendly disposition are required to get and keep a job at this clinic. The Principle Investigator: Dr. Adriana R. Marquees At this point it becomes difficult for me to express my feelings for Dr. Marquees and her associate Dr. Norberto E. Soto. To begin with they took great care and attention with my physical examination. During my stay they spent a good deal of time explaining all aspects of the protocol, it's tests, examinations and procedures. Both doctors listened attentively to what I had to say about my experience with lyme disease. They took the time to answer all my questions about the study and the many aspects of Lyme disease that concern me. The compassion that they showed with regard to the emotional dilemmas that the disease presents me has resulted in my seeking help in addressing this difficult issue. I know that my Lyme world is a much better place with these two in it. When I told some people in the Lyme community that I wanted to tell this positive story and to encourage others to take part in this study, they wanted to know, "how did I benefit from the study?" The first thing I got out of it was hope. Without insurance and unable to work, there seemed to be no way possible for me to get adequate testing for lyme disease. Not to mention co-infection or any of the myriad of afflictions that Lyme disease mimics. Participation in the study has provided me with a full work up of my disease. I was advised as to the status of all my test results while at the clinic and Dr. Marques or Dr. Soto sat and explained what the results meant to me. As some of the tests involve some slow growing cultures, it will be two to three weeks before I know my final status within the protocol. If I qualify for reevaluation, I would certainly look forward to tracking my progress with the disease by going back to Bethesda as is necessary. Just knowing that people like Dr. Marques and Dr. Soto are working at solving some of the great mysteries surrounding Lyme disease has bought me some piece of mind. Having actually been able to sit and talk with them has given me knowledge and confidence as well as hope that I can get through this disease. This has not always been the case. I might also be able to take some small satisfaction in knowing that my participation in the study might help just a little bit in the war against Lyme disease. To learn more about this study, visit: http://www.niaid.nih.gov/recruit/lyme.htm or write to: NIAID Chronic Lyme Disease Study Building 10 Room 11n228 10 Center Drive MSC 1888 Bethesda, MD 20892-1888 or fax: 301-496-7383 For an application to the study call:1 800 772 5464 Ext.605 Please contact me if you have any questions: LindellLee@aol.com The study that Dr. Marques is conducting does not make use of placebos. Thanks for your time and consideration. Please help if you can. No protocol is ideal, but these people are working really hard to help solve some of the mysteries surrounding lyme disease

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