Anton Drollmann

Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial.

Introduction Exercise limitation, dynamic hyperinflation, and exertional dyspnea are key features of symptomatic chronic obstructive pulmonary disease (COPD). We assessed the effects of glycopyrronium bromide (NVA237), a once-daily, long-acting muscarinic antagonist, on exercise tolerance in patients with moderate to severe COPD. Methods Patients were randomized to a cross-over design of once-daily NVA237 50 μg or placebo for 3 weeks, with a 14-day washout. Exercise endurance, inspiratory capacity (IC) during exercise, IC and expiratory volumes from spirometry, plethysmographic lung volumes, leg discomfort and dyspnea under exercise (Borg scales), and transition dyspnea index were measured on Days 1 and 21 of treatment. The primary endpoint was endurance time during a submaximal constant-load cycle ergometry test on Day 21. Results A total of 108 patients were randomized to different treatment groups (mean age, 60.5 years; mean post-bronchodilator, forced expiratory volume in 1 second [FEV1] 57.1% predicted). Ninety-five patients completed the study. On Day 21, a 21% difference in endurance time was observed between patients treated with NVA237 and those treated with placebo (P < 0.001); the effect was also significant from Day 1, with an increase of 10%. Dynamic IC at exercise isotime and trough FEV1 showed significant and clinically relevant improvements from Day 1 of treatment that were maintained throughout the study. This was accompanied by inverse decreases in residual volume and functional residual capacity. NVA237 was superior to placebo (P < 0.05) in decreasing leg discomfort (Borg CR10 scale) on Day 21 and exertional dyspnea on Days 1 and 21 (transition dyspnea index and Borg CR10 scale at isotime). The safety profile of NVA237 was similar to that of the placebo. Conclusion NVA237 50 μg once daily produced immediate and significant improvement in exercise tolerance from Day 1. This was accompanied by sustained reductions in lung hyperinflation (indicated by sustained and significant improvements in IC at isotime), and meaningful improvements in trough FEV1 and dyspnea. Improvements in exercise endurance increased over time, suggesting that mechanisms beyond improved lung function may be involved in enhanced exercise tolerance. (ClinicalTrials.gov Identifier: NCT01154127).

Effect of Indacaterol on Dynamic Lung Hyperinflation and Breathlessness in Hyperinflated Patients with COPD

Abstract: 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.

Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients

NVA237 is a novel, once daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This study aimed to assess the 24-h bronchodilatory effect following 14 days of treatment with inhaled NVA237 in patients with mild, moderate or severe COPD. This was a randomized, double-blind, placebo-controlled, two-period, crossover, multicenter study. A total of 33 patients (≥ 40 years; smoking history of ≥ 10 pack-years) were randomized to receive NVA237 50 μg once daily followed by placebo or placebo followed by NVA237 50 μg for 14 days. Treatment periods were separated by a 7-14 day washout period. The primary variable was the mean forced expiratory volume in 1 s (FEV(1)) derived from the area under the curve (AUC) between 0 and 24 h post-dose on Day 14. The 24-h FEV(1) profiles showed a consistent bronchodilator effect for NVA237 versus placebo on Day 14. Least square (LS) mean difference in FEV(1) AUC(0-24 h) values between NVA237 and placebo was 163 mL (P < 0.001). There were significant increases in mean FEV(1) AUC(0-12 h) (LS mean difference 165 mL, P = 0.001) and FEV(1) AUC(12-24 h) (161 mL, P < 0.001) versus placebo. NVA237 significantly improved peak FEV(1) (by 208 mL, P < 0.001) and trough FEV(1) (by 154 mL, P = 0.003) versus placebo on Day 14. NVA237 was well tolerated; all adverse events were mild or moderate in intensity and not related to study drug. NVA237 50 μg once daily was well tolerated and showed significant and sustained 24-h bronchodilation in patients with COPD.

Cardiac safety of indacaterol in healthy subjects: a randomized, multidose, placebo- and positive-controlled, parallel-group thorough QT study

BackgroundIndacaterol is a novel once-daily ultra long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease. It is known that β2-agonists, like other adrenergic compounds, can prolong the QT-interval. This thorough QT/QTc study (as per ICH E14 guideline) evaluated the effect of indacaterol on the QT interval in healthy subjects.MethodsIn this randomized, double-blind, parallel-group, placebo- and positive-controlled (open-label moxifloxacin) study, non-smoking healthy subjects (18-55 years, body mass index: 18.5-32.0 kg/m2) were randomized (4:4:2:4:1) to 14-day treatment with once-daily indacaterol (150 μg, 300 μg, or 600 μg), placebo, or placebo/moxifloxacin (double-blind 14-day treatment with placebo and a single open-label dose of 400 mg moxifloxacin on Day 14). The primary endpoint was the change from baseline on Day 14 in QTcF (QT interval corrected for heart rate using Fridericias formula).ResultsIn total, 404 subjects were randomized to receive indacaterol (150 [n = 108], 300 [n = 108], 600 μg [n = 54]), placebo (n = 107), or placebo/moxifloxacin (n = 27); 388 subjects completed the study. Maximal time-matched mean (90% confidence intervals) treatment differences from placebo in QTcF change from baseline on Day 14 were 2.66 (0.55, 4.77), 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) ms for indacaterol 150 μg, 300 μg and 600 μg, respectively. Study sensitivity was confirmed with moxifloxacin demonstrating a significant maximal time-matched QTcF prolongation of 13.90 (10.58, 17.22) ms compared to placebo. All indacaterol doses were well tolerated.ConclusionIndacaterol, at doses up to 600 μg once daily (2-4 times the therapeutic dose) does not have any clinically relevant effect on the QT interval.Trial RegistrationClinicalTrials.gov: NCT01263808

Effect of dual bronchodilation with QVA149 on cardiac safety in healthy volunteers.

OBJECTIVES QVA149 is a dual bronchodilator, containing a fixed-dose combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium, for the treatment of chronic obstructive pulmonary disease (COPD). Here we assess the potential of QVA149 (440/200 μg) at 4-fold the therapeutic dose for causing cardiac pharmacodynamic (PD) effects. METHODS This double-blind, randomized study estimated the time-matched largest heart rate (HR) change and average HR change (over 24 hours) from baseline for QVA149 vs. placebo in healthy subjects. Similar analyses were done for QVA149 vs. indacaterol 600 μg, glycopyrronium 200 μg, and salmeterol 200 μg. The time-matched and average change from baseline in QT interval corrected for HR using Fridericias formula (QTcF), effects on serum potassium and blood glucose, pharmacokinetic (PK) parameters, and safety were also assessed. RESULTS Of 50 subjects randomized, 43 completed the study. QVA149, when compared with placebo, showed the time-matched largest mean increase and decrease in HR of 5.69 bpm and -2.51 bpm, respectively, and average HR change from baseline of 0.62 bpm. QVA149 showed no tachycardic potential compared with indacaterol and no relevant tachycardic effect compared with glycopyrronium. No consistent differences were seen in the time-matched largest mean change and average change from baseline in QTcF for QVA149 vs. other treatments. There were no relevant effects of QVA149 on serum potassium and blood glucose. There was no apparent PK/PD relationship between the observed exposures to indacaterol and glycopyrronium in QVA149 on HR and QTcF. There were no deaths or serious adverse events. CONCLUSION Overall, short-term administration of QVA149 showed a good cardiovascular safety and tolerability profile in healthy subjects.

Effect of cimetidine, a model drug for inhibition of the organic cation transport (OCT2/MATE1) in the kidney, on the pharmacokinetics of glycopyrronium.

OBJECTIVE Glycopyrronium (NVA237), a novel once-daily long-acting muscarinic antagonist (LAMA), has recently been approved for maintenance treatment of COPD. This study evaluated the effect of organic cation transporter inhibition on inhaled glycopyrronium disposition using cimetidine as a probe inhibitor. METHODS In this open-label, two-period, two-sequence, crossover study, 20 healthy subjects received two treatments. A single dose of 100 μg glycopyrronium was inhaled alone and on Day 4 of a 6-day treatment with oral cimetidine 800 mg b.i.d. Trough plasma concentrations of cimetidine were determined throughout cimetidine dosing. Plasma concentrations and urinary excretion of glycopyrronium were determined up to 72 hours post glycopyrronium dose. The primary pharmacokinetics (PK) parameters were plasma peak concentration (Cmax), AUC up to the last measured concentration (AUClast), and renal clearance (CLr) of glycopyrronium. RESULTS Cimetidine trough concentrations indicated that PK steady state of cimetidine was reached prior to single dose inhalation of glycopyrronium. Inhalation of glycopyrronium in the presence of cimetidine resulted in an increase in total systemic exposure (AUClast) of glycopyrronium by 22% (geometric mean ratio 1.22; 90% CI: 1.12 - 1.32). This exposure increase correlated with a slight decrease of 23% in CLr (geometric mean ratio 0.77; 90% CI: 0.70 - 0.85). Cmax was not affected. Both treatments were safe and well tolerated without any deaths or severe adverse events. CONCLUSION Based on the magnitude of the PK changes seen in this study, no relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport.

Glycopyrronium does not affect QT interval in healthy subjects: a randomized, three- period, cross-over, placebo- and positive-controlled study.

OBJECTIVE Glycopyrronium (NVA237), a once-daily long-acting muscarinic antagonist, has recently been approved for the treatment of patients with chronic obstructive pulmonary disease (COPD). This study evaluated the effect of glycopyrronium on the QT interval and other cardiac parameters in healthy subjects. METHODS This randomized, partially blinded, single-dose, placebo- and positive- (moxifloxacin) controlled, three-way cross-over study investigated the effect of a single inhaled supra-therapeutic dose (8-fold clinical dose in COPD patients) of 400 µg glycopyrronium on the Fridericia-corrected QT interval (QTcF; primary objective), Bazettcorrected QT interval (QTcB), heart rate, blood pressure, pharmacokinetics (PK), safety, and tolerability. RESULTS A total of 73 healthy male (n = 35) and female (n = 38) subjects, aged between 18 and 45 years, were randomized. Glycopyrronium did not cause significant QTcF prolongation compared to placebo. The largest time-matched mean difference to placebo was 2.97 ms at 5 minutes, with the upper limit of the two-sided 90% confidence interval (CI) being 4.80 ms, excluding a relevant QT effect as defined by the ICH E14 guideline. Glycopyrronium had a slight bradycardic effect with a mean change of -2.88 (90% CI: -3.78, -1.99) beats per minutes (bpm) and a maximum of -5.87 (90% CI: -7.82, -3.92) bpm at 5 hours post-inhalation. No clinically relevant effects were seen on QTcB, other electrocardiogram (ECG) intervals, or blood pressure. Maximum plasma concentration (Cmax) of glycopyrronium was achieved shortly after inhalation (median tmax = 7 minutes). All the treatments were well tolerated with no serious adverse events. CONCLUSION A supra-therapeutic dose of glycopyrronium had a favorable cardiovascular safety profile with no clinically relevant effect on QT interval.

P254 NVA237 once daily improves exercise endurance in patients with COPD from the first dose: the GLOW3 trial

Introduction The fundamental characteristics of COPD are exertional dyspnoea and exercise limitation, which are associated with dynamic hyperinflation. We assessed the effects of NVA237 (glycopyrronium bromide), a once-daily long-acting muscarinic antagonist (LAMA), on exercise endurance in patients with moderate-to-severe COPD. Methods Patients with COPD were randomised to a cross-over design of NVA237 50 μg or placebo once daily for 3 weeks, with a 14-day washout. The primary endpoint was endurance time during a submaximal constant-load cycle ergometry test (SMETT) on Day 21 of treatment. Endurance time after first dose, dynamic hyperinflation (inspiratory capacity [IC] at isotime during exercise), and morning trough FEV1 and plethysmographic lung volumes were also measured. Results 108 patients were randomised; mean age was 60.5 years, mean post-bronchodilator FEV1 was 57.1% predicted. 88.0% completed the study. Endurance time on Day 21 significantly increased by 21% with NVA237 vs placebo; the effect was significant from Day 1, with an increase of 10%. Both dynamic IC at exercise isotime and trough FEV1 showed significant and clinically relevant improvements from Day 1 that were maintained for the study duration (Abstract P254 table 1). This was accompanied by inverse decreases in residual volume and functional residual capacity (Abstract P254 table 1). Overall, the safety profile of NVA237 was similar to that of placebo.Abstract P254 Table 1 NVA237 treatment effects vs placebo NVA237 (LS means, 95% CI) PBO (LS means, 95% CI) NVA237–placebo (LS means diff, 95% CI) p Value Endurance time (s)  Day 1 490.9 (458.5 to 523.4) 447.78 (415.1 to 480.5) 43.1 (10.9 to 75.4) <0.001  Day 21 505.6 (466.6 to 544.7) 416.70 (377.8 to 455.6) 88.9 (44.7 to 133.2) <0.001 IC at isotime (l)  Day 1 2.25 (2.18 to 2.31) 2.02 (1.96 to 2.08) 0.23 (0.17 to 0.28) <0.001  Day 21 2.22 (2.15 to 2.29) 2.02 (1.95 to 2.09) 0.20 (0.13 to 0.28) <0.001 Functional residual capacity (l) % predicted  Day 1 4.41 (4.32 to 4.51) 4.77 (4.67 to 4.86) −0.36 (−0.49 to −0.22) –  Day 21 4.32 (4.22 to 4.42) 4.78 (4.68 to 4.87) −0.46 (−0.58 to −0.33) Residual volume (l)  Day 1 3.49 (3.38 to 3.59) 3.92 (3.82 to 4.02) −0.44 (−0.58 to −0.29) –  Day 21 3.46 (3.36 to 3.55) 3.95 (3.86 to 4.05) −0.50 (−0.63 to −0.36) Total lung capacity (l)  Day 1 7.01 (6.90 to 7.12) 7.08 (6.97 to 7.19) −0.07 (−0.22 to −0.08) –  Day 21 6.86 (6.75 to 6.97) 7.10 (6.99 to 7.21) −0.25 (−0.39 to −0.10) Specific airway conductance (Sec (−1)*kP)  Day 1 0.68 (0.65 to 0.71) 0.41 (0.38 to 0.45) 0.26 (0.22 to 0.30) –  Day 21 0.66 (0.63 to 0.70) 0.42 (0.39 to 0.46) 0.24 (0.19 to 0.29) Trough FEV1 (l)  Day 1 1.46 (1.43 to 1.49) 1.35 (1.31 to 1.38) 0.11 (0.06 to 0.16) <0.001  Day 21 1.44 (1.40 to 1.48) 1.33 (1.29 to 1.37) 0.11 (0.06 to 0.16) <0.001 Conclusion Once-daily NVA237 provided immediate and significant improvement in exercise endurance from Day 1. This was accompanied by sustained and significant improvements in IC at isotime, meaningful improvements in trough FEV1, and sustained reductions of lung hyperinflation. There was an improvement in endurance time during the study period, suggesting that mechanisms beyond improved lung function play a part in superior exercise tolerance.