150 Current Drug Safety, 2012, Vol. 7, No. 2 these clinical trials included electrocardiographic (ECG) recording, providing a large patient subpopulation with documented QTc intervals. A secondary objective, therefore, was to confirm the known QTc prolongation with moxifloxacin and to determine the variability of QTc intervals in the patients included in randomized active- controlled clinical trials with moxifloxacin. PATIENTS AND METHODS Studies Included in the Analysis A pooled analysis was carried out using data from Phase II to IV clinical trials comparing moxifloxacin with other antimicrobials. In all studies, 400 mg of moxifloxacin was administered once daily as monotherapy either PO or sequentially (IV/PO). The PO indications for moxifloxacin were acute bacterial sinusitis (ABS, n = 10 trials), acute exacerbations of chronic bronchitis (AECB, n = 17), CAP (n = 12), uncomplicated skin and skin structure infections (uSSSI, n = 4), uncomplicated pelvic inflammatory disease (uPID, n = 3), uncomplicated urinary tract infections (uUTI, n = 3), complicated urinary tract infections (cUTI, n = 1), and streptococcal pharyngitis (n = 1). The IV/PO trials for moxifloxacin were carried out in patients hospitalized with CAP (n = 7), complicated skin and skin structure infections (cSSSI, n = 3), complicated intra-abdominal infections (cIAI, n = 2), hospital-acquired pneumonia (HAP, n = 2), and aspiration pneumonia or lung abscess (n = 1). A few patients with related indications could be enrolled in two studies, for instance AECB and ABS, and AECB and CAP. In each trial, appropriate PO or IV antimicrobials licensed for the relevant indication were used as the comparator agents; the route of treatment administration may have differed between moxifloxacin and comparator within single trials, as seen in Table 1. Control data are for pooled comparator agents. All control comparators were used at the recommended dose and for the recommended duration – based on the relevant labels at the time and in the region (when and where) the clinical study was conducted – in the applicable indication and adverse events (AEs) were monitored and recorded according to the same standards in all studies, thereby justifying pooling of data in the analysis. Cardiac Safety Populations and Assessments All analyses were performed for the population of patients valid for safety. This included all randomized patients who had received at least one dose of study drug and had one safety assessment. Given the clinical heterogeneity of the PO and IV/PO populations, the two data sets were analyzed separately. All data available in the Bayer HealthCare clinical trial database up to a data lock point of 31 May 2009 were included. Standard safety outcomes recorded in the individual clinical trials were coded using the Medical Dictionary for Regulatory Activities (MedDRA, version 12.0). Cardiac events were defined according to MedDRA preferred terms (PTs) identified using the following Standardized MedDRA Queries: (i) sets of PTs with a primary or secondary path in the System Organ Class ‘Cardiac disorders’; and (ii) sets of Haverkamp et al. PTs that were considered potential surrogates for TdP/QTc prolongation. The MedDRA events (PTs) included as potential surrogates for TdP/QTc prolongation were: cardiac arrest, cardiorespiratory arrest, cardioversion, sudden cardiac death, cardiac death, cardiac flutter, cardiac massage, cardiac fibrillation, death, sudden death, brain death, maternal death affecting fetus, syncope, loss of consciousness, resuscitation, anoxic seizure, TdP, ventricular arrhythmia, ventricular asystole, ventricular fibrillation, ventricular flutter, and ventricular tachycardia. The following safety variables were considered for analysis: treatment-emergent cardiac AEs, treatment- emergent drug-related cardiac AEs, treatment-emergent serious cardiac AEs, treatment-emergent serious drug-related cardiac AEs, treatment-emergent cardiac AEs with fatal outcome, and treatment-emergent drug-related cardiac AEs with fatal outcome. AEs considered as potential surrogates for TdP/QTc prolongation were also analyzed. Treatment-emergent AEs were defined as any AE occurring after the first administration of study drug until the end of follow-up. Cardiac safety variables were analyzed for the overall safety population and two potentially high-risk subgroups with characteristics known to be independently associated with QTc prolongation. These subgroups were women [26- 28] and patients of at least 65 years of age [29]. Treatment-emergent events considered to be potential surrogates for TdP/QTc prolongation were assessed in the overall safety population and further subpopulations at high risk of cardiac arrhythmias and other cardiac AEs: (i) patients on initial IV treatment with CAP requiring admission to the intensive care unit (ICU) and/or mechanical ventilation, (ii) patients with a documented prolonged QTcB interval at baseline (defined as > 450 ms in men or > 470 ms in women), (iii) women, and (iv) patients 65 years old. ECG recordings were carried out in several of the randomized active-controlled trials in approved indications for moxifloxacin that were included in the pooled analysis, including two IV/PO cSSSI studies, five IV/PO CAP studies, and 11 PO ABS, AECB, CAP, cUTI, uPID, and uSSSI studies. The studies included had centralized ECG readings and a standardized methodology was used. QTc data presented here are for patients with valid ECG records (Supplementary material) at baseline, Day 1 and Day 3 (Group A), at baseline and on Day 1 (Group B), or baseline and Day 3 (Group C) of treatment while on IV therapy for CAP or cSSSI. They are presented for patients with paired valid ECG records at baseline and post-baseline in the PO clinical studies. QTc data are available for the overall valid population and for subgroups at higher risk of cardiac events (i.e. women and patients 65 years old). ECG recordings were planned to occur at expected peak plasma concentrations of the antimicrobial (Cmax i.e. PO: approx. 3 h after administration, IV: within 30 min after the end of a 60 minute-infusion). QTcB (QT interval corrected for heart rate and calculated according to Bazett’s formula) and QTcF (QT interval corrected for heart rate and calculated according to Fridericia’s formula) are presented. Of note, both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) require submission of QTc values corrected by using both Bazett and Fridericia formulae.