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

ABSTRACT: 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.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.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%).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.ClinicalTrials.gov number, NCT00473460 (ClincalTrials.gov).

SUBMITTER: Sethi S

PROVIDER: S-EPMC2834642 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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

Sethi Sanjay S Jones Paul W PW Theron Marlize Schmitt MS Miravitlles Marc M Rubinstein Ethan E Wedzicha Jadwiga A JA Wilson Robert R

Respiratory research 20100128

<h4>Background</h4>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.<h4>Methods</h4>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 rep ...[more]

PMID: 20109213

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Project description:RATIONALE:Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous. OBJECTIVES:Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations. METHODS:Subjects with COPD exacerbations were entered into a randomized biomarker-directed double-blind corticosteroid versus standard therapy study. Subjects in the standard arm received prednisolone for 2 weeks, whereas in the biomarker-directed arm, prednisolone or matching placebo was given according to the blood eosinophil count biomarker. Both study groups received antibiotics. Blood eosinophils were measured in the biomarker-directed and standard therapy arms to define biomarker-positive and -negative exacerbations (blood eosinophil count > and ≤ 2%, respectively). The primary outcome was to determine noninferiority in health status using the chronic respiratory questionnaire (CRQ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and standard therapy arms. MEASUREMENTS AND MAIN RESULTS:There were 86 and 80 exacerbations in the biomarker-directed and standard treatment groups, respectively. In the biomarker-directed group, 49% of the exacerbations were not treated with prednisolone. CRQ improvement after treatment in the standard and biomarker-directed therapy groups was similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence interval, 0.0-0.6; P = 0.05). There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone (mean difference, 0.45; 95% confidence interval, 0.01-0.90; P = 0.04). In biomarker-negative exacerbations, treatment failures occurred in 15% given prednisolone and 2% of those given placebo (P = 0.04). CONCLUSIONS:The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required.

Project description:BackgroundIn exacerbations of chronic obstructive pulmonary disease, administration of high concentrations of oxygen may cause hypercapnia and increase mortality compared with oxygen titrated, if required, to achieve an oxygen saturation of 88-92%. Optimally titrated oxygen regimens require two components: titrated supplemental oxygen to achieve the target oxygen saturation and, if required, bronchodilators delivered by air-driven nebulisation. The effect of repeated air vs oxygen-driven bronchodilator nebulisation in acute exacerbations of chronic obstructive pulmonary disease is unknown. We aimed to compare the effects of air versus oxygen-driven bronchodilator nebulisation on arterial carbon dioxide tension in exacerbations of chronic obstructive pulmonary disease.MethodsA parallel group double-blind randomised controlled trial in 90 hospital in-patients with an acute exacerbation of COPD. Participants were randomised to receive two 2.5 mg salbutamol nebulisers, both driven by air or oxygen at 8 L/min, each delivered over 15 min with a 5 min interval in-between. The primary outcome measure was the transcutaneous partial pressure of carbon dioxide at the end of the second nebulisation (35 min). The primary analysis used a mixed linear model with fixed effects of the baseline PtCO2, time, the randomised intervention, and a time by intervention interaction term; to estimate the difference between randomised treatments at 35 min. Analysis was by intention-to-treat.ResultsOxygen-driven nebulisation was terminated in one participant after 27 min when the PtCO2 rose by > 10 mmHg, a predefined safety criterion. The mean (standard deviation) change in PtCO2 at 35 min was 3.4 (1.9) mmHg and 0.1 (1.4) mmHg in the oxygen and air groups respectively, difference (95% confidence interval) 3.3 mmHg (2.7 to 3.9), p < 0.001. The proportion of patients with a PtCO2 change ≥4 mmHg during the intervention was 18/45 (40%) and 0/44 (0%) for oxygen and air groups respectively.ConclusionsOxygen-driven nebulisation leads to an increase in PtCO2 in exacerbations of COPD. We propose that air-driven bronchodilator nebulisation is preferable to oxygen-driven nebulisation in exacerbations of COPD.Trial registrationAustralian New Zealand Clinical Trials Registry number ACTRN12615000389505 . Registration confirmed on 28/4/15.

Project description:BackgroundEarlier detection of chronic obstructive pulmonary disease (COPD) exacerbations may facilitate more rapid treatment with reduced risk of hospitalization. Changes in pulse oximetry may permit early detection of exacerbations. We hypothesized that overnight pulse oximetry would be superior to once-daily monitoring for the early detection of exacerbations.ObjectiveThis study aims to evaluate whether measuring changes in heart rate and oxygen saturation overnight is superior to once-daily monitoring of both parameters and to assess symptom changes in facilitating earlier detection of COPD exacerbations.MethodsA total of 83 patients with COPD were randomized to once-daily or overnight pulse oximetry. Both groups completed the COPD assessment test questionnaire daily. The baseline mean and SD for each pulse oximetry variable were calculated from 14 days of stable monitoring. Changes in exacerbation were expressed as Z scores from this baseline.ResultsThe mean age of the patients was 70.6 (SD 8.1) years, 52% (43/83) were female, and the mean FEV1 was 53.0% (SD 18.5%) predicted. Of the 83 patients, 27 experienced an exacerbation. Symptoms were significantly elevated above baseline from 5 days before to 12 days after treatment initiation. Day-to-day variation in pulse oximetry during the stable state was significantly less in the overnight group than in the once-daily group. There were greater relative changes at exacerbation in heart rate than oxygen saturation. An overnight composite score of change in heart rate and oxygen saturation changed significantly from 7 days before initiation of treatment for exacerbation and had a positive predictive value for exacerbation of 91.2%. However, this was not statistically better than examining changes in symptoms alone.ConclusionsOvernight pulse oximetry permits earlier detection of COPD exacerbations compared with once-daily monitoring. Monitoring physiological variables was not superior to monitoring symptoms, and the latter would be a simpler approach, except where there is a need for objective verification of exacerbations.Trial registrationClinicalTrials.gov NCT03003702; https://clinicaltrials.gov/ct2/show/NCT03003702.

Project description:BACKGROUND: Physical exercise training aims at reducing disease-specific impairments and improving quality of life in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations in particular negatively impact COPD progression. Physical therapy intervention seems indicated to influence exacerbations and their consequences. However, information on the effect of physical therapy on exacerbation occurrence is scarce. This study aims to investigate the potential of a protocol-directed physical therapy programme as a means to prevent or postpone exacerbations, to shorten the duration or to decrease the severity of exacerbations in patients with COPD who have recently experienced an exacerbation. Besides, this study focuses on the effect of protocol-directed physical therapy on health status and quality of life and on cost-effectiveness and cost-utility in patients with COPD who have recently experienced an exacerbation. METHODS/DESIGN: A prospective cohort of 300 COPD patients in all GOLD stages will be constructed. Patients will receive usual multidisciplinary COPD care including guideline-directed physical therapy. Patients in this cohort who have GOLD stage 2 to 4 (post-bronchodilator FEV1/FVC < 0.7 and FEV1 < 80% of predicted), who receive reimbursement by health insurance companies for physical therapy (post-bronchodilator Tiffeneau-index < 0.6) and who experience a COPD exacerbation will be asked within 56 days to participate in a cohort-nested prospective randomised controlled trial (RCT). In this RCT, the intervention group will receive a strict physical therapy programme for patients with COPD. This protocol-directed physical therapy (pdPT) will be compared to a control group that will receive sham-treatment, meaning no or very low-intensity exercise training (ST). An economic evaluation will be embedded in the RCT. Anthropometric measurements, comorbidities, smoking, functional exercise capacity, peripheral muscle strength, physical activity level, health related quality of life, patients' perceived benefit, physical therapy compliance, motivation level, level of effective mucus clearance, exacerbation symptoms and health care contacts due to COPD will be recorded. Follow-up measurements are scheduled at 3 and 6 weeks, 3, 6, 12 and 24 months after inclusion. DISCUSSION: Ways to minimise potential problems regarding the execution of this study will be discussed. TRIAL REGISTRATION: The Netherlands National Trial Register NTR1972.

Project description:IntroductionA substantial majority of chronic obstructive pulmonary disease (COPD)-related morbidity, mortality and healthcare costs are due to acute exacerbations, but existing medications have only a modest effect on reducing their frequency, even when used in combination. Observational studies suggest β-blockers may reduce the risk of COPD exacerbations; thus, we will conduct a randomised, placebo-controlled trial to definitively assess the impact of metoprolol succinate on the rate of COPD exacerbations.Methods and analysesThis is a multicentre, placebo-controlled, double-blind, prospective randomised trial that will enrol 1028 patients with at least moderately severe COPD over a 3-year period. Participants with at least moderate COPD will be randomised in a 1:1 fashion to receive metoprolol or placebo; the cohort will be enriched for patients at high risk for exacerbations. Patients will be screened and then randomised over a 2-week period and will then undergo a dose titration period for the following 6 weeks. Thereafter, patients will be followed for 42 additional weeks on their target dose of metoprolol or placebo followed by a 4-week washout period. The primary end point is time to first occurrence of an acute exacerbation during the treatment period. Secondary end points include rates and severity of COPD exacerbations; rate of major cardiovascular events; all-cause mortality; lung function (forced expiratory volume in 1 s (FEV1)); dyspnoea; quality of life; exercise capacity; markers of cardiac stretch (pro-NT brain natriuretic peptide) and systemic inflammation (high-sensitivity C reactive protein and fibrinogen). Analyses will be performed on an intent-to-treat basis.Ethics and disseminationThe study protocol has been approved by the Department of Defense Human Protection Research Office and will be approved by the institutional review board of all participating centres. Study findings will be disseminated through presentations at national and international conferences and publications in peer-reviewed journals.Trial registration numberNCT02587351; Pre-results.

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

Publications

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

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