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The Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization: an investigator-initiated study protocol for a multicenter, randomized, double-blind, placebo-controlled trial.

ABSTRACT: Long-term use of macrolide antibiotics is effective to prevent exacerbations in chronic obstructive pulmonary disease (COPD). As risks and side effects of long-term intervention outweigh the benefits in the general COPD population, the optimal dose, duration of treatment, and target population are yet to be defined. Hospitalization for an acute exacerbation (AE) of COPD may offer a targeted risk group and an obvious risk period for studying macrolide interventions.Patients with COPD, hospitalized for an AE, who have a smoking history of ?10 pack-years and had ?1 exacerbation in the previous year will be enrolled in a multicenter, randomized, double-blind, placebo-controlled trial (NCT02135354). On top of a standardized treatment of systemic corticosteroids and antibiotics, subjects will be randomized to receive either azithromycin or placebo during 3 months, at an uploading dose of 500 mg once a day for 3 days, followed by a maintenance dose of 250 mg once every 2 days. The primary endpoint is the time-to-treatment failure during the treatment phase (ie, from the moment of randomization until the end of intervention). Treatment failure is a novel composite endpoint defined as either death, the admission to intensive care or the requirement of additional systemic steroids or new antibiotics for respiratory reasons, or the diagnosis of a new AE after discharge.We investigate whether azithromycin initiated at the onset of a severe exacerbation, with a limited duration and at a low dose, might be effective and safe in the highest risk period during and immediately after the acute event. If proven effective and safe, this targeted approach may improve the treatment of severe AEs and redirect the preventive use of azithromycin in COPD to a temporary intervention in the subgroup with the highest unmet needs.

SUBMITTER: Vermeersch K

PROVIDER: S-EPMC4820219 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization: an investigator-initiated study protocol for a multicenter, randomized, double-blind, placebo-controlled trial.

Vermeersch Kristina K Gabrovska Maria M Deslypere Griet G Demedts Ingel K IK Slabbynck Hans H Aumann Joseph J Ninane Vincent V Verleden Geert M GM Troosters Thierry T Bogaerts Kris K Brusselle Guy G GG Janssens Wim W

International journal of chronic obstructive pulmonary disease 20160331

<h4>Background</h4>Long-term use of macrolide antibiotics is effective to prevent exacerbations in chronic obstructive pulmonary disease (COPD). As risks and side effects of long-term intervention outweigh the benefits in the general COPD population, the optimal dose, duration of treatment, and target population are yet to be defined. Hospitalization for an acute exacerbation (AE) of COPD may offer a targeted risk group and an obvious risk period for studying macrolide interventions.<h4>Methods/ ...[more]

PMID: 27099485

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Project description:Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).

Project description:BackgroundIn the BACE trial, a 3-month (3 m) intervention with azithromycin, initiated at the onset of an infectious COPD exacerbation requiring hospitalization, decreased the rate of a first treatment failure (TF); the composite of treatment intensification (TI), step-up in hospital care (SH) and mortality.Objectives(1) To investigate the intervention's effect on recurrent events, and (2) to identify clinical subgroups most likely to benefit, determined from the incidence rate of TF and hospital readmissions.MethodsEnrolment criteria included the diagnosis of COPD, a smoking history of ≥10 pack-years and ≥ 1 exacerbation in the previous year. Rate ratio (RR) calculations, subgroup analyses and modelling of continuous variables using splines were based on a Poisson regression model, adjusted for exposure time.ResultsAzithromycin significantly reduced TF by 24% within 3 m (RR = 0.76, 95%CI:0.59;0.97, p = 0.031) through a 50% reduction in SH (RR = 0.50, 95%CI:0.30;0.81, p = 0.006), which comprised of a 53% reduction in hospital readmissions (RR = 0.47, 95%CI:0.27;0.80; p = 0.007). A significant interaction between the intervention, CRP and blood eosinophil count at hospital admission was found, with azithromycin significantly reducing hospital readmissions in patients with high CRP (> 50 mg/L, RR = 0.18, 95%CI:0.05;0.60, p = 0.005), or low blood eosinophil count (<300cells/μL, RR = 0.33, 95%CI:0.17;0.64, p = 0.001). No differences were observed in treatment response by age, FEV1, CRP or blood eosinophil count in continuous analyses.ConclusionsThis post-hoc analysis of the BACE trial shows that azithromycin initiated at the onset of an infectious COPD exacerbation requiring hospitalization reduces the incidence rate of TF within 3 m by preventing hospital readmissions. In patients with high CRP or low blood eosinophil count at admission this treatment effect was more pronounced, suggesting a potential role for these biomarkers in guiding azithromycin therapy.Trial registrationClinicalTrials.gov number. NCT02135354 .

Project description:BackgroundDespite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness.MethodsWe enrolled adults aged ≥18 years with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis.ResultsFifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%-88%) compared to 62% (95% CI, 32%-86%) for placebo (P = .544). Sixty-day OS was 60% versus 46%, respectively (hazard ratio, 0.66 [95% CI, .22-1.96]; P = .454). Other secondary outcomes were comparable. Duvelisib was associated with lower inflammatory cytokines.ConclusionsIn this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically ill population and was associated with reduction in cytokines implicated in COVID-19 and acute respiratory distress syndrome, supporting further investigation.Clinical trials registrationNCT04372602.

Project description:BackgroundChronic Obstructive Pulmonary Disease (COPD) is a progressive airway disease characterised by neutrophilic airway inflammation or bronchitis. Neutrophilic bronchitis is associated with both bacterial colonisation and lung function decline and is common in exacerbations of COPD. Despite current available therapies to control inflammation, neutrophilic bronchitis remains common. This study tested the hypothesis that azithromycin treatment, as an add-on to standard medication, would significantly reduce airway neutrophil and neutrophils chemokine (CXCL8) levels, as well as bacterial load. We conducted a randomised, double-blind, placebo-controlled study in COPD participants with stable neutrophilic bronchitis.MethodsEligible participants (n?=?30) were randomised to azithromycin 250 mg daily or placebo for 12 weeks in addition to their standard respiratory medications. Sputum was induced at screening, randomisation and monthly for a 12 week treatment period and processed for differential cell counts, CXCL8 and neutrophil elastase assessment. Quantitative bacteriology was assessed in sputum samples at randomisation and the end of treatment visit. Severe exacerbations where symptoms increased requiring unscheduled treatment were recorded during the 12 week treatment period and for 14 weeks following treatment. A sub-group of participants underwent chest computed tomography scans (n?=?15).ResultsNine participants with neutrophilic bronchitis had a potentially pathogenic bacteria isolated and the median total bacterial load of all participants was 5.22×107 cfu/mL. Azithromycin treatment resulted in a non-significant reduction in sputum neutrophil proportion, CXCL8 levels and bacterial load. The mean severe exacerbation rate was 0.33 per person per 26 weeks in the azithromycin group compared to 0.93 exacerbations per person in the placebo group (incidence rate ratio (95%CI): 0.37 (0.11,1.21), p?=?0.062). For participants who underwent chest CT scans, no alterations were observed.ConclusionsIn stable COPD with neutrophilic bronchitis, add-on azithromycin therapy showed a trend to reduced severe exacerbations sputum neutrophils, CXCL8 levels and bacterial load. Future studies with a larger sample size are warranted.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12609000259246.

Dataset Information

The Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization: an investigator-initiated study protocol for a multicenter, randomized, double-blind, placebo-controlled trial.

Publications

The Belgian trial with azithromycin for acute COPD exacerbations requiring hospitalization: an investigator-initiated study protocol for a multicenter, randomized, double-blind, placebo-controlled trial.

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