Lymphangioleiomyomatosis is a rare, progressive cystic lung disorder characterised by dysregulated activation of mammalian target of rapamycin (mTOR) signalling.This was a phase IIa, multicentre, open-label study of the mTOR inhibitor everolimus (2.5 mg·day −1 escalated to 10 mg·day −1 ) in 24 women with lymphangioleiomyomatosis. Primary endpoints were safety, pharmacokinetics and serum vascular endothelial growth factor-D (VEGF-D) levels; secondary endpoints were measures of lung function.Following 26 weeks of everolimus treatment, forced vital capacity exhibited stability, while forced expiration volume in 1 s improved from baseline, with mean changes (95% confidence interval) of 10 mL (−111-132) and 114 mL (11-217), respectively; 6-min walk distance improved by 47 m. Median VEGF-D and collagen IV levels decreased from baseline, from 1730 pg·mL −1 to 934.5 pg·mL, and 103 ng·mL −1 to 80.5 ng·mL, respectively. Adverse events were mostly grade 1−2; mouth ulceration, headache, nausea, stomatitis and fatigue were common. Serious adverse events suspected to be treatment related included peripheral oedema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Everolimus blood levels increased dose proportionally.In this study, everolimus improved some measures of lung function and exercise capacity and reduced serum VEGF-D and collagen IV. Side effects were generally consistent with known toxicities of mTOR inhibitors, although some were severe. @ERSpublications Everolimus improved some lung function measures and reduced serum biomarkers in patients with LAM http://ow.ly/MkQQK

Background The long-acting muscarinic antagonists umeclidinium (UMEC) and tiotropium (TIO) are approved once-daily maintenance therapies for COPD. This study investigated the efficacy and safety of UMEC versus TIO in COPD. Methods This was a 12-week, multicenter, randomized, blinded, double-dummy, parallel-group, non-inferiority study. Patients were randomized 1:1 to UMEC 62.5 μg plus placebo or TIO 18 μg plus placebo. The primary end point was trough forced expiratory volume in 1 second (FEV 1 ) at day 85 (non-inferiority margin −50 mL; per-protocol [PP] population). Other end points included weighted mean FEV 1 over 0–24 and 12–24 hours post-dose. Patient-reported outcomes comprised Transition Dyspnea Index score, St George’s Respiratory Questionnaire total score, and COPD Assessment Test score. Adverse events were also assessed. Results In total, 1,017 patients were randomized to treatment. In the PP population, 489 and 487 patients received UMEC and TIO, respectively. In the PP population, change from baseline in trough FEV 1 was greater with UMEC versus TIO at day 85, meeting non-inferiority and superiority margins (difference: 59 mL; 95% confidence interval [CI]: 29–88; P <0.001). Similar results were observed in the intent-to-treat analysis of trough FEV 1 at day 85 (53 mL, 95% CI: 25–81; P <0.001). Improvements in weighted mean FEV 1 over 0–24 hours post-dose at day 84 were similar with UMEC and TIO but significantly greater with UMEC versus TIO over 12–24 hours post-dose (70 mL; P =0.015). Clinically meaningful improvements in Transition Dyspnea Index and St George’s Respiratory Questionnaire were observed with both treatments at all time points. No differences were observed between UMEC and TIO in patient-reported outcomes. Overall incidences of adverse events were similar for UMEC and TIO. Conclusion UMEC 62.5 μg demonstrated superior efficacy to TIO 18 μg on the primary end point of trough FEV 1 at day 85. Safety profiles were similar for both treatments.

Indacaterol is a novel, inhaled once-daily ultra long-acting β2-agonist for the treatment of COPD. This randomised, double-blind, placebo-controlled, two-period crossover study evaluated the effect of two-week treatment with indacaterol 300 μg on peak and isotime exercise inspiratory capacity (IC) in patients with COPD. Patients (40-80 years) with post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 70%, percent predicted FEV1 ≥ 40% and ≤ 80%, smoking history ≥ 20 pack-years and functional residual capacity > 120% of predicted normal were randomised to receive indacaterol 300 μg or placebo once-daily via a single-dose dry powder inhaler. Following 14 days of treatment, IC at peak and isotime during constant-load (80% of maximum workload) cycle ergometry was analysed using linear mixed-effects models. Safety and tolerability were also monitored. Twenty-seven patients (67% male; mean age, 61.3 years) were randomised; 24 completed the study. On Day 14, indacaterol showed statistically significant improvements over placebo in peak (317 mL [95% CI: 118-517]; p < 0.01) and isotime IC (268 mL [95% CI: 104-432]; p < 0.01). Statistically significant improvements were observed with indacaterol versus placebo on Day 14 for the following secondary endpoints: resting IC, trough FEV1, dyspnoea (BDI/TDI and Borg CR10 scale at isotime) and exercise endurance time. Indacaterol was well tolerated, with no serious adverse events or deaths. In conclusion, indacaterol 300 μg administered once-daily showed a clinically relevant increase in IC after 14 days of treatment, reflecting a reduction in dynamic hyperinflation.

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