Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial - 18/04/17

Doi : 10.1016/S1473-3099(16)30529-1

Michael Schwameis, MD ^a, Thomas Kündig, ProfMD ^b, Gustave Huber, PhD ^c, Luzi von Bidder, MSc ^c, Lorenz Meinel, ProfPhD ^d, Roland Weisser, MD ^e, Elisabeth Aberer, ProfMD ^f, Georg Härter, MD ^g,^h, Thomas Weinke, ProfMD ⁱ, Tomas Jelinek, ProfMD ^j, Gerd Fätkenheuer, ProfMD ^k, Uwe Wollina, ProfMD ^l, Gerd-Dieter Burchard, ProfMD ^m, Roland Aschoff, MD ⁿ, Ruth Nischik ^o, Gerhard Sattler, MD ^p, Georg Popp, MD ^q, Wolfgang Lotte, MD ^r, Dirk Wiechert, MD ^s, Gerald Eder, MD ^t, Olga Maus, MD ^u, Petra Staubach-Renz, ProfMD ^v, Andrea Gräfe, MD ^w, Veronika Geigenberger, MD ^x, Ingomar Naudts, MD ^y, Michael Sebastian, MD ^z, Norbert Reider, ProfMD ^aa, Ridwan Weber, MD ^ab, Marc Heckmann, ProfMD ^ac, Emil C Reisinger, ProfMD ^ad, Georg Klein, ProfMD ^ae, Johannes Wantzen, MD ^af, Bernd Jilma, ProfMD ^a,^⁎

^a Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

^b Clinical Trial Centre, Department of Dermatology, University of Zurich, Zurich, Switzerland

^c Ixodes, Zumikon, Switzerland

^d Institut für Pharmazeutische Technologie und Biopharmazie, Am Hubland, Würzburg, Germany

^e Sihlmed Dermatology, Zurich, Switzerland

^f Department of Dermatology, Medical University of Graz, Graz, Austria

^g Medicover Ulm MVZ, Ulm, Germany

^h Universitätsklinikum Ulm, Ulm, Germany

ⁱ Klinikum Ernst von Bergmann, Gastroenterology and Infectious Disease, Potsdam, Germany

^j Berliner Centrum für Reise und Tropenmedizin, Berlin, Germany

^k Department I of Internal Medicine, University Hospital Cologne, German Center for Infection Research (DZIF), Cologne, Germany

^l Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany

^m Bernd Nocht Institute for Tropical Medicine, Hamburg, Germany

ⁿ Klinik und Poliklinik für Dermatologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany

^o Medamed, Leipzig, Germany

^p Rosenpark Research, Darmstadt, Germany

^q Licca Clinical Research Institute, Augsburg, Germany

^r HNO Praxis, Iserlohn, Germany

^s Praxis, Bremen, Germany

^t Zentrum für Reisemedizin, St Pölten, Austria

^u Innomed Leipzig, Leipzig, Germany

^v Department of Dermatology, Johannes Gutenberg University, Mainz, Germany

^w Dermatologie Northeim, Northeim, Germany

^x Neurologie Dachau, Dachau, Germany

^y Praxis Rodgau, Rodgau, Germany

^z Dermatologie Mahlow, Blankenfelde-Mahlow, Germany

^aa Department of Dermatology and Venerology, Medical University Innsbruck, Innsbruck, Austria

^ab MVZ Hochzoll, Augsburg, Germany

^ac Dermatologie, Starnberg-Percha, Germany

^ad Division of Tropical Medicine and Infectious Diseases, Center of Internal Medicine II, University of Rostock, Rostock, Germany

^ae Department of Dermatology and Venerology, Krankenhaus Elisabethinen Linz, Linz, Austria

^af Centre for Travel Medicine and Occupational Health, Bad Kreuznach, Germany

^* Correspondence to: Prof Bernd Jilma, Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria Department of Clinical Pharmacology Medical University of Vienna Waehringer Guertel 18–20 Vienna A-1090 Austria

Summary

Background

Lyme borreliosis develops in 1–5% of individuals bitten by ticks, but with a diagnostic gap affecting up to 30% of patients, a broadly applicable pharmacological prevention strategy is needed. Topical azithromycin effectively eradicated Borrelia burgdorferi sensu lato from the skin in preclinical studies. We assessed its efficacy in human beings.

Methods

In this randomised, double-blind, placebo-controlled, multicentre trial done in 28 study sites in Germany and Austria, adults were equally assigned to receive topical 10% azithromycin or placebo twice daily for 3 consecutive days, within 72 h of a tick bite being confirmed. Randomisation numbers, which were stratified by study site, were accessed in study centres via an interactive voice-response system, by pharmacists not involved in the study. The primary outcome was the number of treatment failures, defined as erythema migrans, seroconversion, or both, in participants who were seronegative at baseline, had no further tick bites during the study, and had serology results available at 8 weeks (intention-to-treat [ITT] population). This study is registered with EudraCT, number 2011-000117-39.

Findings

Between July 7, 2011, and Dec 3, 2012, 1371 participants were randomly assigned to treatment, of whom 995 were included in the ITT population. The trial was stopped early because an improvement in the primary endpoint in the group receiving azithromycin was not reached. At 8 weeks, 11 (2%) of 505 in the azithromycin group and 11 (2%) of 490 in the placebo group had treatment failure (odds ratio 0·97, 95% CI 0·42–2·26, p=0·47). Topical azithromycin was well tolerated. Similar numbers of patients had adverse events in the two groups (175 [26%] of 505 vs 177 [26%] of 490, p=0·87), and most adverse events were mild.

Interpretation

Topical azithromycin was well tolerated and had a good safety profile. Inclusion of asymptomatic seroconversion into the primary efficacy analysis led to no prevention effect with topical azithromycin. Adequately powered studies assessing only erythema migrans should be considered. A subgroup analysis in this study suggested that topical azithromycin reduces erythema migrans after bites of infected ticks.

Funding

Ixodes AG.

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Plan

Introduction

Methods

Study design and participants

Randomisation and masking

Procedures

Outcomes

Statistical analysis

Role of the funding source

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Vol 17 - N° 3

P. 322-329 - mars 2017 Retour au numéro

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Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial - 18/04/17

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