Efficacy and Safety of Aclidinium Bromide Compared with Placebo and Tiotropium in Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease: Results from a 6-week, Randomized, Controlled Phase Iiib Study

Figures & data

Figure 1. Patient disposition. AE, adverse event; BID, twice daily; QD, once daily.

Table 1.  Demographics and baseline characteristics of the study population (safety population)

	Placebo (N = 85)	Aclidinium 400 μg BID (N = 171)	Tiotropium 18 μg QD (N = 158)
Gender (male), n (%)	48 (56.5)	114 (66.7)	116 (73.4)
Age (years), mean (SD)	62.2 (8.2)	61.8 (8.2)	62.8 (7.9)
Race, n (%)
White	84 (98.8)	171 (100)	158 (100)
Asian	1 (1.2)	0 (0)	0 (0)
BMI (kg/m^2), mean (SD)	26.7 (4.9)	27.5 (4.9)	27.6 (4.8)
Current smoker, n (%)	47 (53.3)	93 (54.4)	84 (53.2)
Smoking consumption (pack‑years), mean (SD)	39.6 (15.4)	41.5 (22.4)	45.0 (21.8)
COPD duration (years), mean (SD)	9.6 (6.7)	8.8 (5.9)	8.2 (6.0)
Post-bronchodilator FEV1 (L)
Mean (SD)	1.57 (0.52)	1.61 (0.50)	1.67 (0.54)
% predicted, mean (SD)	55.5 (11.8)	55.8 (13.3)	56.0 (13.2)
COPD severity,^a,b n (%)
Moderate	58 (68.2)	108 (63.2)	104 (66.2)
Severe	27 (31.8)	63 (36.8)	53 (33.8)

^aGOLD Stage II (moderate): FEV₁/FVC < 0.70, and post-bronchodilator FEV₁ ≥ 50% and < 80% predicted; GOLD Stage III (severe): FEV₁/FVC < 0.70, and post-bronchodilator FEV₁ ≥ 30% and < 50% predicted.

^bCOPD severity was missing for one patient in the tiotropium treatment group at screening (pre- and post-salbutamol values determined to be unacceptable following review).

BID, twice daily; BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; QD, once daily; SD, standard deviation.

Figure 2. Change from baseline in FEV₁ AUC_0–24, FEV₁ AUC_12–24, and FEV₁ AUC_0–12 compared with placebo (A) on day 1 and (B) at week 6 (ITT population). Data reported as LS mean (95% CI) differences from placebo (ANCOVA). ^‡p < 0.001; ^§p < 0.0001 for aclidinium or tiotropium versus placebo. ^¶p < 0.05; ^#p < 0.01 for aclidinium versus tiotropium. ANCOVA, analysis of covariance; AUC, area under the curve; AUC_0–24, AUC over the 24-hour period post-morning treatment; AUC_12–24, AUC over the nighttime period; AUC_0–12, AUC for the 12-hour period post-morning treatment; BID, twice daily; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; ITT, intent-to-treat; LS, least squares; QD, once daily.

Figure 3. Change from baseline in FEV₁ over 24 hours (A) on day 1 and (B) at week 6. Data reported as LS mean change from baseline (ANCOVA). p < 0.01 for aclidinium and tiotropium versus placebo at each time point. ^¶p < 0.05; ^#p < 0.01; ^∥p < 0.001; ^¶¶p < 0.0001 for aclidinium versus tiotropium. ANCOVA, analysis of covariance; BID, twice daily; FEV₁, forced expiratory volume in 1 second; LS, least squares; QD, once daily.

Table 2.  Change from baseline (difference from placebo) in additional lung-function variables (ITT population)

	Aclidinium 400 μg BID (N = 171)	Tiotropium 18 μg QD (N = 158)	Δ (aclidinium vs tiotropium)
Morning pre-dose (trough) FEV1 (mL)
Day 1	141^§	93^‡	48^¶
Week 6	141^§	102^‡	38
Peak FEV1 (mL)
Day 1	154^§	139^§	14
Week 6	180^§	172^§	8
Morning pre-dose (trough) FVC (mL)
Day 1	212^§	127^†	84^¶
Week 6	223^§	144^†	79
Peak FVC (mL)
Day 1	201^§	146^§	54
Week 6	212^§	170^†	42

Data reported as LS mean differences from placebo (ANCOVA).

^†p < 0.01; ^‡p < 0.001; ^§p < 0.0001 for aclidinium or tiotropium versus placebo.

^¶p < 0.05 for aclidinium versus tiotropium.

ANCOVA, analysis of covariance; BID, twice daily; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; ITT, intent-to-treat; LS, least squares; QD, once daily.

Figure 4. Change from baseline in E-RS total and domain scores over 6 weeks. Data reported as LS mean (95% CI) difference from placebo (ANCOVA). *p < 0.05; ^†p < 0.01; ^§p < 0.0001 for aclidinium or tiotropium versus placebo. ANCOVA, analysis of covariance; BID, twice daily; CI, confidence interval; E-RS, EXAcerbations of Chronic pulmonary disease Tool (EXACT)-Respiratory Symptoms; LS, least squares; QD, once daily.

Figure 5. Difference from placebo in change from baseline in (A) severity of early-morning symptoms, (B) severity of nighttime symptoms and number of nocturnal awakenings due to COPD symptoms, and (C) limitation of activity caused by COPD symptoms (COPD additional symptoms questionnaire) over 6 weeks (ITT population). Data reported as LS mean differences from placebo (ANCOVA). *p < 0.05; ^†p < 0.01; ^‡p < 0.001 for aclidinium or tiotropium versus placebo. ^¶p < 0.05 for aclidinium versus tiotropium. Severity of overall early-morning and nighttime symptoms rated on a 5-point scale from 1 = ‘did not experience any symptoms’ to 5 = ‘very severe’; individual morning symptoms rated on a 5-point scale from 0 = ‘no symptoms’ to 4 = ‘very severe’; limitation of activity rated on a 5-point scale from 1 = ‘not at all’ to 5 = ‘a very good deal’. ANCOVA, analysis of covariance; BID, twice daily; COPD, chronic obstructive pulmonary disease; ITT, intent-to-treat; LS, least squares; QD, once daily.

Table 3.  Patient preference for each inhaler based on specific inhaler attributes at week 6, n (%)

	No. of patients (%)
Attribute	Genuair	HandiHaler	No preference
Ease of use	357 (86.7)	37 (9.0)	18 (4.4)
Convenience	360 (87.4)	32 (7.8)	20 (4.9)
Ease of learning to use	326 (79.1)	33 (8.0)	53 (12.9)
Ease of holding	329 (79.9)	35 (8.5)	48 (11.7)
Ease of operating	334 (81.1)	38 (9.2)	40 (9.7)
Ease of dose preparation	356 (86.4)	32 (7.8)	24 (5.8)
Feedback to indicate correct inhalation	314 (76.2)	39 (9.5)	59 (14.3)

For all attributes, p < 0.0001 for Genuair versus HandiHaler (exact binomial test).