Vestbo et al. [10] studied, in a double-blind, double-dummy, cross-over design, the percentage of patients with an increase in FEV₁ ≥ 10% above baseline at 30 minutes post dose. Significantly more patients reached the end-point with aclidinium and tiotropium vs placebo (49.5% and 51.8% vs 13.8%; p<0.0001); and aclidinium and tiotropium significantly improved FEV₁ compared with placebo at all measured points from 10 minutes to 3 hours post-dose. The rate of onset of bronchodilation of aclidinium is, based on the present study, at least as fast as for tiotropium.

The safety profile of aclidinium bromide was studied based on pooled data from ACCLAIM/COPD I and ACCLAIM /COPD II by Jones et al. [10]. The overall incidence of adverse events was similar in the aclidinium and placebo groups, apart from a higher frequency of dry mouth in the groups treated with aclidinium. In the clinical studies published so far cardiac and vascular disorders were reported at a similar frequency in the aclidinium and placebo groups [11,12].

The study by Joos et al. [13] enrolled patients with an FEV₁ < 65% of predicted value and bronchodilator reversibility > 12% and 200mL. The mean area under the FEV₁ curve (primaru outcome) over the 0-24 h time interval was 1.58 L for placebo, and 1.72 L, 1.79 L, and 1.82 L for aclidinium 100, 300, 900 μg, respectively (p<0.001 vs placebo, all doses). The authors concluded that aclidinium bromide 100-900 μg produces sustained bronchodilatation over 24 h in patients with moderate to severe COPD. In keeping with this, the ACCLAIM/COPD I and ACCLAIM/COPD II published by Jones et al. [11] revealed a trough FEV₁ at 12 and 28 weeks of aclidinium bromide versus vs placebo of 61 ml and 67 ml (both p<0.001), and 63 ml and 59 ml (both p<0.001), respectively, in the two studies.

Chanez et al. [14] aimed at establishing the optimal dose of aclidinium bromide in COPD patients with an FEV₁ of 30 to 65%pred. Aclidinium bromide at doses of 200 μg and 400 μg and tiotropium bromide were statistically significant more effective than placebo in increasing through FEV₁ at day 29. Adjusted mean differences compared with placebo in through FEV₁ for aclidinium were 148 ml (200 μg) and 128 ml (400 μg), and for tiotropium 161 ml. In line with this Singh et al. [15] studied, in a double-blind, double-dummy, placebo- and active comparator controlled crossover design, the mean change from baseline in FEV₁ normalised area under the curve (AUC)_0-12 on day 7. After 7 days of treatment, aclidinium and formoterol produced statistically significant greater change from baseline in FEV₁ normalised AUC_0-12vs placebo; and, furthermore, the study confirmed the twice-daily aclidinium dosing regimen and aclidinium 200 μg and 400 μg as suitable doses for further investigation. Furthermore, the study by Fuhr et al. [16] showed that aclidinium bromide 400 μg twice-daily compared with placebo provided clinically meaningful in 24-h bronkodilatation that generally were comparable to the effect of tiotropium bromide, but with statistically significant differences in favour of aclidinium bromide observed in the night-time period.

In the ACCORD I/COPD study including COPD patients with a mean baseline FEV₁ of 47 %pred., Kerwin et al. [17] showed that Aclidinium bromide 200 μg and 400 μg significantly improved mean (95%CI) trough FEV₁, compared with placebo, by 86 (45, 127) ml and 124 (83,164) ml, respectively, and peak FEV₁ by 146 (101, 190) ml and 192 (148, 236) ml, respectively (p< 0.0001).

From the ATTAIN study of COPD patients with a mean baseline FEV₁ of 53 %pred, Jones et al. [18] reported a significant improvement from baseline with aclidinium 200 μg and 400 μg vs placebo for trough FEV₁ (99 and 128 ml; p< 0.0001) and peak FEV₁ (185 and 209 ml; p< 0.0001). Furthermore, the observed improvement in peak FEV₁ on day 1 was comparable with that on week 24.

Maltais et al. [19] investigated exercise capacity in COPD patients with a mean post-bronchodilator FEV₁ approximately 50%pred, and functional residual capacity ≥ 120%pred. At screening, all patients underwent symptom-limited cycle ergometry with increasing work-load in 10 W increments in order to determine the maximum tolerated workload; and constant work rate cycling exercises at 75% of peak work rate were performed at baseline, day 1, week 3, and week 6 (primary end-point). Patients treated with aclidinium had, compared with placebo, significantly greater improvement in exercise endurance time (mean ± SE of 129 ± 31 s for aclidinium vs 13 ± 31 s for placebo). Furthermore, the study by Maltais et al. [19] also revealed a significant treatment difference from baseline in trough inspiratory capacity (IC) and IC/total lung capacity, and by that suggesting a beneficial effect on dynamic hyperinflation

Chanez et al. [14] reported a decrease in the total St. George Respiratory Questionnaire (SGRQ) score, and by that improved, from baseline with all doses of aclidinium. The percentage of patients with meaningful improvement in SGRQ total score ≥ 4 points from baseline ranged from 53% in the 400 μg group to 64% in the 100 μg group; the improvements in SGRQ score were mainly due to changes in the symptom and impact components. Data, however, on corresponding improvements among patients treated with placebo and tiotropium, and by that makes it extremely difficult to draw valid conclusions with regard to the effect on health status. Furthermore, statistically significant increases in Transition Dyspnoea Index (TDI) were also reported for aclidinium 100 μg and 400 μg compared with placebo, but no exact data were reported, including whether the minimal clinical significance were reached, and no statistically significant difference compared with placebo were observed in any treatment group in the magnitude of the effort component. Overall, there were no significant differences between active treatment and placebo in the mean number of days with self-reported symptoms of dyspnoea, cough, wheeze, sputum or daily doses of rescue salbutamol. In contrast to this, Singh et al. [15] reported that daily use of relief medication was lower with all doses of aclidinium and with formoterol compared with placebo; treatment difference in number of daily puffs of relief medication was up to -0.48 for aclidinium (p<0.05) and -0.67 for formoterol (p<0.05).

The ACCLAIM/COPD I study [11] showed that significantly more patients receiving aclidinium had an improvement in SGRQ total score ≥ 4 units compared with placebo at all measured time points, although the percentage of patients achieving this improvement was 48% and 40%, respectively for aclidinium and placebo, appears lower than in the study by Chanez et al. [14]. Furthermore, in the ACCLAIM/COPD II study [11], no significant difference in percentage of patients achieving an improvement in SGRQ total score ≥ 4 units was found between aclidinium (39%) and placebo (33%) at week 52. In line with this, the ACCLAIM/COPD I study [11] showed that compared with placebo significant more patients treated with aclidinium exceeded the minimal clinical important difference (MCID) for TDI focal score at 52 weeks (aclidinium 56% vs placebo 38%; p< 0.0001), whereas no significant difference in TDI focal score was found in the ACCLAIM/COPD II study, possibly due to the very high drop-out rate in the latter study. Overall, no general significant differences between aclidinium and placebo was observed in the two studies reported by Jones et al. [11] with regard to daily symptom scores or use of rescue medication. The ATTAIN study [18] showed a significant improvements in health status, assessed by SGRQ, daily use of relief medication, and TDI focal score in patients treated with aclidinium compared with placebo.

Fuhr et al. [16] reported a significant decline in use of relief medication with both aclidinium and tiotropium compared with placebo, with no significant difference between aclidinium and tiotropium. Furthermore, compared with placebo, aclidinium significantly reduced breathlessness (p=0.026) and cough (p=0.039); night-time COPD symptom score, assessed on a scale from 0 to 4, were significantly reduced by aclidinium compared with placebo at day 15 (p=0.049), whereas no significant change was observed with tiotropium [16]. In line with this, the study by Kerwin et al. [17] reported a significant reduction in frequency of night-time symptoms, including breathlessness and wheezing, severity and impact of breathlessness and cough on night-time activity, impact of breathlessness on early morning activity, and frequency of night-time awakenings.

Jones et al. [10] reported from the ACCLAIM/COPD II study that fewer in the aclidinium group experienced a moderate (defined as treatment with antibiotics and/or systemic corticosteroid) or severe (defined as hospitalisation) exacerbation compared with those in the placebo group (33% vs 40%; p=0.0046); and that aclidinium significantly delayed the time to first moderate or severe exacerbation. However, in the ACCLAIM/COPD I study [10], the proportion of patients having a moderate or severe exacerbation was similar in the aclidinium and placebo groups (27% vs 26%). The study by Kerwin et al. [17] observed a trend towards a reduction in moderate to severe COPD exacerbation rates with aclidinium compared with placebo, although the study was not powered to assess exacerbation frequency. The ATTAIN study [18] reported, compared with placebo, a lower rate of exacerbations in patients treated with aclidinium.