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Contemporary Clinical Trials Volume 33, Issue 6, November 2012, Pages 1132–1142 Antibiotic retreatment of Lyme disease in patients with persistent symptoms: A biostatistical review of randomized, placebo-controlled, clinical trials Allison K. DeLonga, , , Barbara Blossomb, Elizabeth L. Maloneyc, Steven E. Phillipsd a Center for Statistical Sciences, Department of Biostatistics, Brown University, Providence, RI, USA b Department of Statistics, Colorado State University, Fort Collins, CO, USA c Partnership for Healing and Health, Ltd., Wyoming, MN, USA d Greenwich Hospital, Greenwich, CT, USA Received 4 May 2012 Revised 16 July 2012 Accepted 14 August 2012 Available online 19 August 2012 http://dx.doi.org/10.1016/j.cct.2012.08.009, How to Cite or Link Using DOI Permissions & Reprints Abstract Introduction Lyme disease (Lyme borreliosis) is caused by the tick-borne spirochete Borrelia burgdorferi. Long-term persistent illness following antibiotic treatment is not uncommon, particularly when treatment is delayed. Current treatment guidelines for persistent disease primarily rely on findings from four randomized, controlled trials (RCTs), strongly advising against retreatment. Methods We performed a biostatistical review of all published RCTs evaluating antibiotic retreatment, focusing on trial design, analysis and conclusions. Results Four RCTs met the inclusion criteria; all examined the efficacy of intravenous ceftriaxone versus placebo at approximately 3 or 6 months. Design assumptions for the primary outcomes in the two Klempner trials and two outcomes in the Krupp trial were unrealistic and the trials were likely underpowered to detect clinically meaningful treatment effects. The Klempner trials were analyzed using inefficient statistical methods. The Krupp RCT was well-designed and analyzed for fatigue, finding statistically significant and clinically meaningful improvement. Fallon corroborated this finding. Fallon also found improvement in cognitive functioning, a primary outcome, at 12 weeks which was not sustained at 24 weeks; improvements in physical functioning and pain were demonstrated at week 24 as an interaction effect between treatment and baseline symptom severity with the drug effect increasing with higher baseline impairment. Discussion This biostatistical review reveals that retreatment can be beneficial. Primary outcomes originally reported as statistically insignificant were likely underpowered. The positive treatment effects of ceftriaxone are encouraging and consistent with continued infection, a hypothesis deserving additional study. Additional studies of persistent infection and antibiotic treatment are warranted. Keywords Lyme disease; Neuroborreliosis; Randomized controlled trial; Statistical power; Minimum clinically important difference (MCID); Treatment guidelines Figures and tables from this article: Full-size image (73 K) Fig. 1. Flow diagram of the literature search for randomized, controlled trials evaluating antibiotic retreatment in Lyme disease patients with persistent symptoms following a standard course of treatment. Figure options Table 1. Available measures of treatment effects for each trial and outcome. NS effect not given, reported as not statistically significant.“–”Within-arm effects were not reported for each trial. Table options View in workspace Table 2. SF-36 summary score changes found to be clinically and statistically significant for chronic diseases of similar severity to Lyme disease. ‡ Not determined; § Not significant. Table options View in workspace Table 3. Estimated differences in the proportion of patients expected to be classified as improved using Klempner et al.'s categorization for various mean treatment effects consistent with published MCIDs. Klempner et al.'s results are provided and confirm clinically meaningful mean differences of 2 to 5 points fall within Klempner et al.'s 95% confidence intervals [16]. Table options View in workspace Table 4. Mean response times of Lyme patients and controls on the Alphabet Arithmetic test (Pollina et al., Table 3) [39] and the differences in the two groups presented as the percentage faster that healthy participants completed the task compared to the Lyme patients. 1 In the STOP-LD study design, Krupp et al. [24] assumed a 25% improvement as the MCID.2 Age- and education-matched controls. Table options View in workspace Corresponding author at: Center for Statistical Sciences, Department of Community Health, Brown University, Providence, RI 02912, USA. Tel.: + 1 401 863 9697; fax: + 1 401 863 9182. Copyright © 2012 Elsevier Inc. All rights reserved. Jacques Szefner jszefner@aol.com

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