Effect of Aclidinium Bromide on Exacerbations in Patients with Moderate-to-Severe COPD: A Pooled Analysis of Five Phase III, Randomized, Placebo-Controlled Studies

Figures & data

Table 1. Study designs.

Study name	ClinicalTrials.gov registration	Treatment weeks	Treatment arms	Randomized patients
Monotherapy
ACCORD I	NCT00891462	12	Aclidinium 400 μg BID, Aclidinium 200 μg BID, Placebo	561
ACCORD II	NCT01045161	12	Aclidinium 400 μg BID, Aclidinium 200 μg BID, Placebo	544
ATTAIN	NCT01001494	24	Aclidinium 400 μg BID, Aclidinium 200 μg BID, Placebo	828
Combination therapy
ACLIFORM	NCT01462942	24	Aclidinium/formoterol 400/12 μg BID, Aclidinium/formoterol 400/6 μg BID, Aclidinium 400 μg BID, Formoterol 12 μg BID, Placebo	1,729
AUGMENT	NCT01437397	24	Aclidinium/formoterol 400/12 μg BID, Aclidinium/formoterol 400/6 μg BID, Aclidinium 400 μg BID, Formoterol 12 μg BID, Placebo	1,692

BID, twice-daily.

Table 2. Patient demographics and baseline characteristics (ITT population).

	ACCORD I	ACCORD II	ATTAIN	ACLIFORM	AUGMENT	Pooled placebo arms	Pooled aclidinium 400 μg BID arms	Overall
Number of patients	375^a	359^a	542^a	577^a	668^a	1,165	1,356	2,521^a
Age, years, mean (SD)	65.0 (9.4)	62.4 (9.2)	62.4 (8.2)	63.5 (8.1)	63.9 (8.8)	63.2 (8.7)	63.6 (8.7)	63.4 (8.7)
Male (%)	52.0	52.6	68.5	67.9	54.3	59.8	60.0	59.9
Current smoker (%)	44.5	53.2	53.9	47.5	50.9	51.2	49.3	50.1
Smoking history, pack-years, mean (SD)	55.1 (28.4)	53.4 (28.0)	40.3 (19.8)	39.7 (19.9)	52.7 (27.3)	47.9 (25.9)	47.2 (25.1)	47.5 (25.5)
Post-bronchodilator FEV1 (% predicted)	54.4 (13.2)	52.7 (13.3)	56.4 (12.5)	54.0 (13.2)	52.8 (13.3)	54.7 (13.3)	53.6 (13.0)	54.1 (13.2)
COPD severity (GOLD stage) (%)
Stage I (mild)	0.0	0.6	0.0	0.0	0.3	0.2	0.1	0.2
Stage II (moderate)	61.7	53.8	67.3	59.2	54.3	59.9	58.6	59.2
Stage III (severe)	37.7	45.7	32.7	40.6	44.7	39.5	41.0	40.3
Stage IV (very severe)	0.5	0.0	0.0	0.2	0.8	0.4	0.2	0.3
Patients with ≥1 exacerbation prior to study entry (%)	25.3	24.0	34.4	36.4	20.5	26.4	30.0	28.3
Patients with SGRQ total score ≥25 (%)	88.0	88.9	89.5	88.2	84.4	87.0	88.1	87.5

^aIncludes patients in the aclidinium 400 μg and placebo arms.

BID, twice-daily; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; GOLD, Global initiative for chronic Obstructive Lung Disease; ITT, intent-to-treat; SD, standard deviation; SGRQ, St. George's Respiratory Questionnaire.

Figure 1. Pooled analysis population, stratified by GOLD group (ITT population). ^aPatients had FEV₁ 30–80% predicted. There were 62 patients with insufficient data for GOLD classification. ITT, intent-to-treat; GOLD, Global initiative for chronic Obstructive Lung Disease; N, number of patients in aclidinium 400 μg and placebo groups.

Figure 2. Concomitant ICS use by study and overall (ITT population). ICS, inhaled corticosteroid; ITT, intent-to-treat; N, number of patients in aclidinium 400 μg and placebo groups.

Table 3. Patients with ≥1 exacerbation.

	Monotherapy			Combination therapy
	3-month studies		6-month studies
	ACCORD I	ACCORD II	ATTAIN	ACLIFORM	AUGMENT	Overall
Number of patients	375	359	542	579^a	669^a	2,521^a
Patients with ≥1 exacerbation of any severity, %
Aclidinium 400 μg	6.3	10.7	14.1	10.9	17.5	12.5
Placebo	11.9	10.4	20.5	13.4	18.1	15.7
OR vs. placebo	0.51	0.95	0.64	0.78	0.96	0.78
p-value	0.073	0.886	0.051	0.361	0.848	0.039
Patients with ≥1 moderate-to-severe exacerbation, %
Aclidinium 400 μg	5.8	9.6	12.3	8.8	15.7	10.9
Placebo	8.6	10.4	16.1	10.8	16.6	13.3
OR vs. placebo	0.65	0.82	0.73	0.79	0.94	0.82
p-value	0.292	0.584	0.206	0.423	0.768	0.116

^aExacerbations analyses from the individual ACLIFORM and AUGMENT studies are reported for the ITT-exacerbations populations (579 and 669 patients, respectively; all patients who received at least one dose of the study medication), as specified in the study protocols and published previously (20,32); pooled analyses include data from the ITT populations (577 and 668 patients, respectively; all patients who received at least one dose of the study medication and had a baseline and ≥1 post-baseline FEV₁ assessment) for consistency with the ACCORD I, ACCORD II and ATTAIN study populations.

ITT, intent-to-treat; OR, odds ratio

Figure 3. Rate of COPD exacerbations of any severity (A) overall (individual studies and pooled analyses)^a and (B) stratified by GOLD group (pooled analysis). ^aExacerbations analyses from the individual ACLIFORM and AUGMENT studies are reported for the ITT-exacerbations populations of the aclidinium monotherapy and placebo arms only (579 and 669 patients, respectively; all patients who received at least one dose of the study medication), as specified in the study protocols and published previously (20,32); pooled analyses include data from the ITT populations (577 and 668 patients, respectively; all patients who received at least one dose of the study medication and had a baseline and ≥1 post-baseline FEV₁ assessment) for consistency with the ACCORD I, ACCORD II and ATTAIN study populations. Percentages are the proportion of all GOLD-classified patients (N  =  2,459) in each GOLD group. CI, confidence interval; COPD, chronic obstructive pulmonary disease; GOLD, Global initiative for chronic Obstructive Lung Disease; ITT, intent-to-treat; RR, rate ratio; N, number of patients in aclidinium 400 μg and placebo groups.

Figure 4. Rate of moderate-to-severe COPD exacerbations (A) overall (individual studies and pooled analyses)^a and (B) stratified by GOLD group (pooled analysis). ^aExacerbations analyses from the individual ACLIFORM and AUGMENT studies are reported for the ITT-exacerbations populations of the aclidinium monotherapy and placebo arms only (579 and 669 patients, respectively; all patients who received at least one dose of the study medication), as specified in the study protocols and published previously (20,32); pooled analyses include data from the ITT populations (577 and 668 patients, respectively; all patients who received at least one dose of the study medication and had a baseline and ≥1 post-baseline FEV₁ assessment) for consistency with the ACCORD I, ACCORD II and ATTAIN study populations. Percentages are the proportion of all GOLD-classified patients (N  =  2,459) in each GOLD group. CI, confidence interval; GOLD, Global initiative for chronic Obstructive Lung Disease; ITT, intent-to-treat; RR, rate ratio; N, number of patients in aclidinium 400 μg and placebo groups.

Table 4. Exacerbation rates stratified by concomitant ICS use (ITT population).

	Overall	ICS	No ICS
Rate of exacerbations of any severity (per patient per year)
Aclidinium 400 μg, N  =  1,356	0.41	0.54	0.32
Placebo, N  =  1,165	0.52	0.67	0.42
RR vs. placebo	0.79	0.80	0.77
p-value	0.026	0.117	0.090
Rate of moderate-to-severe exacerbations (per patient per year)
Aclidinium 400 μg, N  =  1,356	0.35	0.46	0.27
Placebo, N  =  1,165	0.44	0.57	0.35
RR vs. placebo	0.80	0.82	0.76
p-value	0.044	0.194	0.117

ICS, inhaled corticosteroid; ITT, intent-to-treat; N, number of patients; RR, rate ratio.

Figure 5. Time to first COPD exacerbation of any severity in (A) all patients; (B) patients in GOLD Groups A and C; and (C) patients in GOLD Groups B and D (ITT population). COPD, chronic obstructive pulmonary disease; GOLD, Global initiative for chronic Obstructive Lung Disease; HR, hazard ratio; ITT, intent-to-treat; N, number of patients.