Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial

Abstract

Background: Acute exacerbations contribute to the morbidity and mortality associated with chronic obstructive pulmonary disease (COPD). This proof-of-concept study evaluates whether intermittent pulsed moxifloxacin treatment could reduce the frequency of these exacerbations.

Methods: Stable patients with COPD were randomized in a double-blind, placebo-controlled trial to receive moxifloxacin 400 mg PO once daily (N = 573) or placebo (N = 584) once a day for 5 days. Treatment was repeated every 8 weeks for a total of six courses. Patients were repeatedly assessed clinically and microbiologically during the 48-week treatment period, and for a further 24 weeks' follow-up.

Results: At 48 weeks the odds ratio (OR) for suffering an exacerbation favoured moxifloxacin: per-protocol (PP) population (N = 738, OR 0.75, 95% confidence interval (CI) 0.565-0.994, p = 0.046), intent-to-treat (ITT) population (N = 1149, OR 0.81, 95% CI 0.645-1.008, p = 0.059), and a post-hoc analysis of per-protocol (PP) patients with purulent/mucopurulent sputum production at baseline (N = 323, OR 0.55, 95% CI 0.36-0.84, p = 0.006).There were no significant differences between moxifloxacin and placebo in any pre-specified efficacy subgroup analyses or in hospitalization rates, mortality rates, lung function or changes in St George's Respiratory Questionnaire (SGRQ) total scores. There was, however, a significant difference in favour of moxifloxacin in the SGRQ symptom domain (ITT: -8.2 vs -3.8, p = 0.009; PP: -8.8 vs -4.4, p = 0.006). Moxifloxacin treatment was not associated with consistent changes in moxifloxacin susceptibility. There were more treatment-emergent, drug related adverse events with moxifloxacin vs placebo (p < 0.001) largely due to gastrointestinal events (4.7% vs 0.7%).

Conclusions: Intermittent pulsed therapy with moxifloxacin reduced the odds of exacerbation by 20% in the ITT population, by 25% among the PP population and by 45% in PP patients with purulent/mucopurulent sputum at baseline. There were no unexpected adverse events and there was no evidence of resistance development.

Trial registration: ClinicalTrials.gov number, NCT00473460 (ClincalTrials.gov).

Figure 1

Progression of patients through the study.

Figure 2

Frequency distribution of exacerbations. Data are after 48 weeks of intermittent therapy in (a) the per-protocol end-of-treatment (PP EOT) population and (b) the intent-to-treat (ITT) population.

Figure 3

Clinical efficacy of moxifloxacin vs placebo. (a) Per-protocol end-of-treatment (PP EOT) and intent-to-treat (ITT) populations according to the primary and secondary definitions of an exacerbation, and (b) patients with purulent/mucopurulent sputum at baseline (PP EOT and ITT populations using the primary definition of an exacerbation). The first set of p-values on the graphs are from logistic regression analysis using the median value for patients missing at 48 weeks. Corresponding p-values for logistic regression analysis using last observation carried forward are given in brackets. AECB, acute exacerbation of chronic bronchitis.

Figure 4

Changes in St George's Respiratory Questionnaire symptom subscale scores. (a) Per-protocol end-of-treatment (PP EOT) population using a minimum clinically important difference (MCID) of 4 units; (b) PP EOT population using an MCID of 8 units; (c) intent-to-treat (ITT) population using an MCID of 4 units; (D) ITT population using an MCID of 8 units.

Figure 5

Median MIC for moxifloxacin for Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa. Data are shown for the entire 72 weeks of the study: 48 weeks of intermittent therapy and 24 weeks of follow-up. S, screening visit; R, randomization visit; EOT, end-of-treatment visit; MIC, minimum inhibitory concentration; numbers in the table are of patients with an isolate at a given time point.