Azithromycin during Acute Chronic Obstructive Pulmonary Disease Exacerbations Requiring Hospitalization (BACE). A Multicenter, Randomized, Double-Blind, Placebo-controlled Trial.

Rationale: Azithromycin prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPDs); however, its value in the treatment of an AECOPD requiring hospitalization remains to be defined.Objectives: We investigated whether a 3-month intervention with low-dose azithromycin could decrease treatment failure (TF) when initiated at hospital admission and added to standard care.Methods: In an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, patients who had been hospitalized for an AECOPD and had a smoking history of ≥10 pack-years and one or more exacerbations in the previous year were randomized (1:1) within 48 hours of hospital admission to azithromycin or placebo. The study drug (500 mg/d for 3 d) was administered on top of a standardized acute treatment of systemic corticosteroids and antibiotics, and subsequently continued for 3 months (250 mg/2 d). The patients were followed for 6 months thereafter. Time-to-first-event analyses evaluated the TF rate within 3 months as a novel primary endpoint in the intention-to-treat population, with TF defined as the composite of treatment intensification with systemic corticosteroids and/or antibiotics, a step-up in hospital care or readmission for respiratory reasons, or all-cause mortality.Measurements and Main Results: A total of 301 patients were randomized to azithromycin (n = 147) or placebo (n = 154). The TF rate within 3 months was 49% in the azithromycin group and 60% in the placebo group (hazard ratio, 0.73; 95% confidence interval, 0.53-1.01; P = 0.0526). Treatment intensification, step-up in hospital care, and mortality rates within 3 months were 47% versus 60% (P = 0.0272), 13% versus 28% (P = 0.0024), and 2% versus 4% (P = 0.5075) in the azithromycin and placebo groups, respectively. Clinical benefits were lost 6 months after withdrawal.Conclusions: Three months of azithromycin for an infectious AECOPD requiring hospitalization may significantly reduce TF during the highest-risk period. Prolonged treatment seems to be necessary to maintain clinical benefits.

Dual bronchodilation with tiotropium/olodaterol further reduces activity-related breathlessness versus tiotropium alone in COPD.

The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD).This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index <8. Patients received 6 weeks of tiotropium/olodaterol 5/5 µg and tiotropium 5 µg in a randomised order with a 3-week washout period. The speed for the 3-min CSST was determined for each patient such that an intensity of breathing discomfort ≥4 ("somewhat severe") on the modified Borg scale was reached at the end of a completed 3-min CSST.After 6 weeks, there was a decrease in the intensity of breathlessness (Borg dyspnoea score) at the end of the 3-min CSST from baseline with both tiotropium (mean -0.968, 95% CI -1.238- -0.698; n=100) and tiotropium/olodaterol (mean -1.325, 95% CI -1.594- -1.056; n=101). The decrease in breathlessness was statistically significantly greater with tiotropium/olodaterol versus tiotropium (treatment difference -0.357, 95% CI -0.661- -0.053; p=0.0217).Tiotropium/olodaterol reduced activity-related breathlessness more than tiotropium in dyspnoeic patients with moderate to severe COPD exhibiting lung hyperinflation.

Treatment failure and hospital readmissions in severe COPD exacerbations treated with azithromycin versus placebo - a post-hoc analysis of the BACE randomized controlled trial.

BACKGROUND: In 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. METHODS: Enrolment 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. RESULTS: Azithromycin 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. CONCLUSIONS: This 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 REGISTRATION: ClinicalTrials.gov number. NCT02135354 .

Sustained 24-hour efficacy of once daily indacaterol (300 µg) in patients with chronic obstructive pulmonary disease: a randomized, crossover study.

PURPOSE: Indacaterol is a novel, once daily, inhaled ultra-long-acting ß2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). Here we compared the 24-h spirometry profile of once daily indacaterol 300 µg with that of placebo and twice daily salmeterol 50 µg in patients with COPD. METHODS: This randomized, multicenter, placebo-controlled, crossover study comprised three 14-day treatment periods (with 14-day washouts). Patients (male/female ≥ 40 years) with moderate-to-severe COPD were randomized to receive double-blind indacaterol 300 µg or placebo once daily, or open-label salmeterol 50 µg twice daily. The primary outcome measure was 24-h post-dose (trough) FEV1 (mean of FEV1 at 23 h 10 min and 23 h 45 min post-indacaterol dose) after 14 days. FEV1 was assessed at multiple time points on Days 1 and 14 of each treatment period. Safety and tolerability were also monitored. RESULTS: Of 68 randomized patients, 61 completed. Trough FEV1 (primary endpoint) on Day 14 for indacaterol was 200 mL higher than placebo (p < 0.001), exceeding the prespecified minimum clinically important difference (120 mL), and was 90 mL higher than for salmeterol (p = 0.011). After Day 1, trough FEV(1) for indacaterol was 150 mL higher than placebo (p < 0.001). Indacaterol provided superior bronchodilation compared with placebo (p < 0.001) across the full 24-h assessment period on Days 1 and 14. In addition, on both days, indacaterol provided superior FEV1 compared with salmeterol (p < 0.05) at many post-baseline time points, including 5 min post-dose. All treatments were well tolerated. CONCLUSIONS: Once daily indacaterol 300 µg produced effective sustained 24-h bronchodilation from the first dose, an efficacy profile superior to placebo and twice daily salmeterol. Given its effective bronchodilation with once daily dosing, indacaterol is likely to be a useful treatment option for patients with moderate-to-severe COPD.

Monomeric CRP is Elevated in Patients with COPD Compared to Non-COPD Control Persons.

Chronic low-grade systemic inflammation is frequently observed in patients with chronic obstructive pulmonary disease (COPD), e.g., elevated pentameric CRP (pCRP). However, pCRP can dissociate to form monomeric CRP (mCRP) which exhibits a clear pro-inflammatory behaviour in contrast to the more anti-inflammatory properties of pCRP. Therefore, mCRP may be an informative biomarker to demonstrate chronic low-grade systemic inflammation. This was confirmed by analysing serum samples from 38 patients with COPD and 18 non-COPD control persons (NCCP). mCRP was significantly elevated in patients with COPD vs. NCCP, indicating that mCRP might be considered as a new sensitive marker of chronic low-grade systemic inflammation.

Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD.

BACKGROUND: The combination of short-acting beta(2)-agonists and anticholinergics in the treatment of COPD has been well documented, but data on combination of long-acting agents are lacking. METHODS: A randomized, open-label, placebo-controlled, three-way crossover study was conducted comparing 2-week treatment periods of tiotropium alone to tiotropium plus formoterol once or twice daily following a 2-week pretreatment period with tiotropium. Lung function (FEV(1), FVC, and resting inspiratory capacity [IC]) serially over 24 h was measured in 95 patients with stable COPD at baseline and after 2 weeks of each treatment. RESULTS: Mean baseline FEV(1) was 1.05 L (38% of predicted). There was a circadian variation in FEV(1), FVC, and IC at baseline that was maintained during all treatment periods. Average FEV(1) (0 to 24 h) improved by 0.08 L with tiotropium, by 0.16 L with tiotropium plus formoterol once daily, and by 0.20 L with tiotropium plus formoterol twice daily (p < 0.01 for all comparisons). Compared with tiotropium alone, add-on formoterol in the morning produced improvement in FEV(1), FVC, and IC for > 12 h. The second add-on dose of formoterol in the evening caused further improvement in FEV(1) for 12 h, but in FVC and IC for < 12 h. Peak increase in FEV(1) was 0.23 L (22% of baseline) with tiotropium and 0.39 L (37% of baseline) with tiotropium plus formoterol (p < 0.0001). Compared with tiotropium alone, add-on formoterol once and twice daily reduced the use of rescue salbutamol during the daytime (p < 0.01) and with add-on formoterol twice daily also during the nighttime (p < 0.05). The combination of tiotropium and formoterol was well tolerated. CONCLUSION: In the treatment of COPD, there is benefit from adding formoterol once or twice daily to tiotropium once daily in terms of improvement in airflow obstruction, resting hyperinflation, and the use of rescue salbutamol.

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.

BACKGROUND: 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. METHODS/DESIGN: 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. DISCUSSION: 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.

A randomised, double-blind, four-way, crossover trial comparing the 24-h FEV1 profile for once-daily versus twice-daily treatment with olodaterol, a novel long-acting ß2-agonist, in patients with chronic obstructive pulmonary disease.

BACKGROUND: This randomised, double-blind, four-way, crossover, Phase II study compared the 24-h forced expiratory volume in 1 s (FEV1) profile of alternative dosing frequencies of two total daily doses of olodaterol (5 and 10 µg) in patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients received olodaterol 2 µg twice daily (BID), 5 µg BID, 5 µg once daily (QD) and 10 µg QD in a randomised sequence over 3-week treatment periods. Co-primary end points were FEV1 area under the curve from 0 to 12 h (AUC0-12) and area under the curve from 12 to 24 h (AUC12-24) responses. Additional lung-function responses, pharmacokinetics and safety were assessed. RESULTS: 47 patients were treated. All olodaterol doses provided significant increases in FEV1 versus baseline (p < 0.001) and FEV1 time profiles were nearly identical for olodaterol 5 and 10 µg QD. Olodaterol 5 µg QD demonstrated improved FEV1 AUC0-12 and similar AUC12-24 versus 2 µg BID. Olodaterol 5 µg QD showed slightly increased FEV1 AUC0-12 but lower AUC12-24 compared to 5 µg BID. Bronchodilation over 24 h was similar for olodaterol 5 µg QD and BID. All doses were well tolerated. CONCLUSIONS: Olodaterol 5 µg QD is efficacious in COPD, with a superior bronchodilatory profile compared to 2 µg BID, which is close to the same total daily dose, and a similar degree of bronchodilation over 24 h compared with double the daily dose (administered as 10 µg QD or 5 µg BID). TRIAL REGISTRATION: ClinicalTrials.gov: NCT00846768.

Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study.

BACKGROUND: Addition of a second bronchodilator from a different pharmacological class may benefit patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) whose symptoms are insufficiently controlled by bronchodilator monotherapy. GLOW6 evaluated the efficacy and safety of once-daily coadministration of the long-acting ß2-agonist indacaterol (IND) and the long-acting muscarinic antagonist glycopyrronium (GLY) versus IND alone in patients with moderate-to-severe COPD. MATERIALS AND METHODS: In this randomized, double-blind, parallel group, placebo-controlled, 12-week study, patients were randomized 1:1 to IND 150 µg and GLY 50 µg daily (IND + GLY) or IND 150 µg daily and placebo (IND + PBO) (all delivered via separate Breezhaler® devices). The primary objective was to demonstrate the superiority of IND + GLY versus IND + PBO for trough forced expiratory volume in 1 second (FEV1) at week 12. Other end points included trough FEV1 at day 1, FEV1 area under the curve from 30 minutes to 4 hours (AUC30min-4h), peak FEV1, inspiratory capacity and trough forced vital capacity (FVC) at day 1 and week 12, and transition dyspnea index (TDI) focal score, COPD symptoms, and rescue medication use over 12 weeks. RESULTS: A total of 449 patients were randomized (IND + GLY, 226; IND + PBO, 223); 94% completed the study. On day 1 and at week 12, IND + GLY significantly improved trough FEV1 versus IND + PBO, with treatment differences of 74 mL (95% CI 46-101 mL) and 64 mL (95% CI 28-99 mL), respectively (both P<0.001). IND + GLY significantly improved postdose peak FEV1, FEV1 AUC30min-4h, and trough FVC at day 1 and week 12 versus IND + PBO (all P<0.01). TDI focal score and COPD symptoms (percentage of days able to perform usual daily activities and change from baseline in mean daytime respiratory score) were significantly improved with IND + GLY versus IND + PBO (P<0.05). The incidence of adverse events was similar for the two treatment groups. CONCLUSION: In patients with moderate-to-severe COPD, once-daily coadministration of IND and GLY provides significant and sustained improvement in bronchodilation versus IND alone from day 1, with significant improvements in patient-centered outcomes.