Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial.

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.

A Novel multivalent OspA vaccine against Lyme borreliosis is safe and immunogenic in an adult population previously infected with Borrelia burgdorferi sensu lato.

Lyme borreliosis (LB) patients who recover, as well as previously infected asymptomatic individuals, remain vulnerable to reinfection with Borrelia burgdorferi sensu lato. There is limited information available about the use of OspA vaccines in this population. In this study, a randomized double-blind phase I/II trial was performed to investigate the safety and immunogenicity of a novel multivalent OspA vaccine in healthy adults who were either seronegative or seropositive for previous B. burgdorferi sensu lato infection. The participants received three monthly priming immunizations with either 30 µg or 60 µg alum-adjuvanted OspA antigen and a booster vaccination either 6 months or 9 to 12 months after the first immunization. The antibody responses to the six OspA serotypes included in the vaccine were evaluated. Adverse events were predominantly mild and transient and were similar in the seronegative and seropositive populations. Substantial enzyme-linked immunosorbent assay (ELISA) and surface-binding antibody responses against all six OspA antigens were induced after the primary immunization schedule in both populations, and they were substantially increased with both booster schedules. The antibody responses induced by the two doses were similar in the seronegative population, but there was a significant dose response in the seropositive population. These data indicate that the novel multivalent OspA vaccine is well tolerated and immunogenic in individuals previously infected with B. burgdorferi sensu lato. (This study is registered at ClinicalTrials.gov under registration no. NCT01504347.).

The novel TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma.

BACKGROUND: Allergen-specific TH2 responses contribute to the development of allergic asthma. Their increase may be due to a reduced early exposure to environmental pathogens, which induces a TH1 response, and thereby suppresses the allergic TH2 response. QbG10 (bacteriophage Qbeta-derived virus-like particle with CpG-motif G10 inside), a novel Toll-like receptor 9 agonist packaged into virus-like particles, was designed to stimulate the immune system toward a TH1-mediated protective response. OBJECTIVE: We examined clinical efficacy, safety, and tolerability of QbG10 with patient-reported and objective clinical outcome parameters in patients with mild-to-moderate persistent allergic asthma. METHODS: In this proof-of-concept parallel-group, double-blind, randomized trial, 63 asthmatic patients followed conversion to a standardized inhaled steroid and were treated with 7 injections of either QbG10 or placebo. Incorporating a controlled steroid withdrawal, the effects on patient-reported (day- and nighttime asthma symptoms, salbutamol usage, and 7-item-Asthma Control Questionnaire scores) and objective clinical outcome measures (FEV1, fraction of exhaled nitric oxide, and blood eosinophils) were assessed over 12 weeks (ClinicalTrials.gov number, NCT00890734). RESULTS: All patient-reported parameters improved overall between week 0 and 12 in QbG10-treated patients (n = 33) despite steroid withdrawal, compared with deteriorations observed under placebo (n = 30, P < .05). At week 12, two thirds of the QbG10-treated patients had their asthma "well controlled" (Asthma Control Questionnaire score ≤0.75) compared with one third under placebo. FEV1 had worsened to a clinically significant extent in patients on placebo, while it remained stable in QbG10 patients. Adverse events were mostly injection site reactions occurring after QbG10 administration. CONCLUSION: Treatment with QbG10 may contribute to continued asthma control during steroid reduction in patients on moderate or high-dose inhaled steroids.

Introducing candesartan 32 mg plus hydrochlorothiazide 25 mg in previously untreated patients with severe essential hypertension.

PURPOSE: To investigate the efficacy of candesartan 32 mg and hydrochlorothiazide (HCTZ) 25 mg combination in patients with severe essential hypertension. PATIENTS AND METHODS: In this prospective, open-label, single-group study, 106 previously untreated patients with a baseline systolic blood pressure (SBP) of 150-200 mmHg, and a diastolic blood pressure (DBP) of 110 to 120 mmHg, started with candesartan 16 mg during the first week. HCTZ 12.5 mg was added at week 2 and from fourth week onwards candesartan 32 mg plus HCTZ 25 mg was given over 6 weeks. The primary efficacy endpoint was mean reduction in SBP and DBP after 9 weeks. Response was defined as a decrease in SBP to <140 mmHg and/or by ≥20 mmHg and in DBP to <90 mmHg and/or by ≥10 mmHg. A second response criterion defined blood pressure reduction below 140/90 mmHg. RESULTS: Blood pressure was lowered from 180.0 ± 11.7/114.7 ± 3.1 mmHg by SBP 44.4 ± 16.8 and DBP 32.0 ± 11.3 mmHg (P < 0.0001). Response was 92.4% and 64.8% achieved <140/90 mmHg. Each titration step produced a statistically significant and clinically relevant decrease in SBP and DBP, but a level below 140/90 mmHg was achieved by >50% of the patients only after the third titration step. Adverse reactions were reported by 3.8% of the patients. The disorders were in line with the known safety profile of the study drugs. CONCLUSION: A stepped treatment approach with candesartan/HCTZ combinations is effective and safe to achieve a swift blood pressure reduction in newly diagnosed, severe hypertension. The target of <140/90 mmHg was reached by >50% of the patients only after taking the full dose of candesartan 32 mg and HCTZ 25 mg.