Efficacy, Safety, and Tolerability of Aclidinium Bromide in the Treatment of Moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD) (LAS-MD-38)

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01045161
• Collaborator: (none)
• Enrollment: 544
• Locations: 112
• Arms: 3
• Duration (Months): 27
• Patients Per Site: 4.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy, safety and tolerability of aclidinium bromide doses compared with placebo in the treatment of moderate to severe, stable chronic obstructive pulmonary disease. The study will be 56 weeks in duration; a 2-week run-in period followed by a 12-week double-blind, placebo-controlled treatment period. This will be followed by an open-label 40-week treatment period and a 2-week follow up phone call. All patients will receive the higher Aclidinium Bromide during the 40-week open label treatment period.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: Aclidinium bromide; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 544 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Tolerability of 2 Doses of Aclidinium Bromide Compared With Placebo for 12 Weeks in Patients With Moderate to Severe, Stable Chronic Obstructive Pulmonary Disease Followed by a 40-Week Evaluation of the Higher Aclidinium Bromide Dose
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Aclidinium bromide 200 μg dose twice per day, inhaled for 12 weeks of treatment At week 12, patients who were on Aclidinium bromide 200 μg will receive open label 400µg aclidinium bromide for 40 weeks	Drug: Aclidinium bromide; Aclidinium bromide 200 μg, oral inhalation twice per day 12 weeks of treatment. At week 12, patients who were on Aclidinium bromide 200 μg will receive open label 400µg aclidinium bromide for 40 weeks of treatment.
Experimental: 2 Aclidinium bromide 400 μg dose twice per day, inhaled for 12 weeks of treatment. At week 12, patients who were on Aclidinium bromide 400 μg will continue to receive open label 400µg aclidinium bromide for 40 weeks	Drug: Aclidinium bromide; Aclidinium bromide 200 μg, oral inhalation twice per day 12 weeks of treatment. At week 12, patients who were on Aclidinium bromide 200 μg will receive open label 400µg aclidinium bromide for 40 weeks of treatment.
Placebo Comparator: 3 Dose-match placebo, oral inhalation twice per day for 12 weeks of treatment. At week 12, patients who were on placebo will receive open label 400µg aclidinium bromide for 40 weeks	Drug: Placebo; Dose-matched placebo, oral inhalation twice per day for 12 weeks. At week 12, patients who were on placebo will receive open label 400 µg aclidinium bromide for 40 weeks of treatment

Outcome Measures

Primary Outcome Measures

1. Part A: Morning Predose (Trough) Forced Expiratory Volume in 1 Second (FEV1) [Change from baseline (Week 0) to Week 12]

   Change from baseline in Trough forced expiratory volume in 1 second before the morning dose of aclidinium bromide, Last Observation Carried Forward (LOCF)

2. Part B: Morning Predose (Trough) FEV1 [Change from baseline (Week 0) to 52 Weeks]

   Change from Baseline in Morning Pre-dose (trough) Forced Expiratory Volume in 1 Second (FEV1) at Week 52, Lost Observation Carried Forward (LOCF)

Secondary Outcome Measures

1. Part A: Peak Forced Expiratory Volume in 1 Second (FEV1) [Change from baseline (Week 0) to Week 12]

   Change from baseline in peak FEV1 at week 12, Last Observation Carried Forward (LOCF)

2. Part B: Peak FEV1 [Change from baseline (Week 0) to 52 Weeks]

   Change from Baseline in Peak FEV1 (L) at Week 52, Last Observation Carried Forward (LOCF)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• A diagnosis of stable moderate to severe COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, 2008; postbronchodilator FEV1/FVC < 70%, and postbronchodilator FEV1 ≥ 30% and < 80% predicted

• Current or former cigarette smokers

Exclusion Criteria:

• Patients who have been hospitalized for an acute COPD exacerbation within 3 months before the first visit

• Respiratory tract infection or COPD exacerbation in the 6 weeks before Visit 1

• Patient with any clinically significant respiratory conditions other than COPD, cardiovascular conditions or mental illness

• History or presence of asthma verified from medical records

• Chronic use of oxygen therapy greater than or equal to 15 hours per day

• Patient with uncontrolled infection due to HIV and/or active hepatitis

• Patients with a history of hypersensitivity reaction to inhaled anticholinergics

• Patients with clinically significant cardiovascular conditions, including myocardial infarction during the previous 6 months, newly diagnosed arrhythmia within the previous 3 months, unstable angina, unstable arrhythmia that had required changes in pharmacological therapy or other intervention.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site 1493	Birmingham	Alabama	United States	35209
2	Forest Investigative Site 1419	Birmingham	Alabama	United States	35233
3	Forest Investigative Site 1413	Muscle Shoals	Alabama	United States	35662
4	Forest Investigative Site 1353	Pell City	Alabama	United States	35128
5	Forest Investigative Site 1379	Phoenix	Arizona	United States	85018
6	Forest Investigative Site 2065	Fullerton	California	United States	92835
7	Forest Investigative Site 1451	National City	California	United States	91950
8	Forest Investigative Site 1388	Paramount	California	United States	90723
9	Forest Investigative Site 1424	Rolling Hill Estates	California	United States	90274
10	Forest Investigative Site 1427	Sacramento	California	United States	95817
11	Forest Investigative Site 1418	San Diego	California	United States	92120
12	Forest Investigative Site 2009	San Diego	California	United States	92120
13	Forest Investigative Site 1374	Torrance	California	United States	90505
14	Forest Investigative Site 1331	Vista	California	United States	92083
15	Forest Investigative Site 1380	Golden	Colorado	United States	80401
16	Forest Investigative Site 1447	Pueblo	Colorado	United States	81001
17	Forest Investigative Site 1364	Clearwater	Florida	United States	33756
18	Forest Investigative Site 1516	Edgewater	Florida	United States	32132
19	Forest Investigative Site 1403	Hollywood	Florida	United States	33021
20	Forest Investigative Site 1485	Homestead	Florida	United States	33032
21	Forest Investigative Site 1352	Miami	Florida	United States	33126
22	Forest Investigative Site 1391	Naples	Florida	United States	34110
23	Forest Investigative Site 1376	Port Orange	Florida	United States	32129
24	Forest Investigative Site 1372	South Miami	Florida	United States	33143
25	Forest Investigative Site 1407	Trinity	Florida	United States	34655
26	Forest Investigative Site 1185	Winter Park	Florida	United States	32789
27	Forest Investigative Site 1386	Atlanta	Georgia	United States	30328
28	Forest Investigative Site 1411	Calhoun	Georgia	United States	30701
29	Forest Investigative Site 1528	Lawrenceville	Georgia	United States	30046
30	Forest Investigative Site 0679	Coeur d' Alene	Idaho	United States	83814
31	Forest Investigative Site 1385	Elk Grove Village	Illinois	United States	60007
32	Forest Investigative Site 1409	O'Fallon	Illinois	United States	62269
33	Forest Investigative Site 1479	Anderson	Indiana	United States	46011
34	Forest Investigative Site 2022	Evansville	Indiana	United States	47714
35	Forest Investigative Site 1441	Indianapolis	Indiana	United States	46256
36	Forest Investigative Site 1149	South Bend	Indiana	United States	46617
37	Forest Investigative Site 1406	Iowa City	Iowa	United States	52240
38	Forest Investigative Site 1080	Topeka	Kansas	United States	66606
39	Forest Investigative Site 2033	Bowling Green	Kentucky	United States	42101
40	Forest Investigative Site 1090	Hazard	Kentucky	United States	41701
41	Forest Investigative Site 1430	New Orleans	Louisiana	United States	70115
42	Forest Investigative Site 1446	New Orleans	Louisiana	United States	70119
43	Forest Investigative Site 1360	Sunset	Louisiana	United States	70584
44	Forest Investigative Site 1412	Baltimore	Maryland	United States	21201
45	Forest Investigative Site 1518	North East	Maryland	United States	21901
46	Forest Investigative Site 1442	Brockton	Massachusetts	United States	02301
47	Forest Investigative Site 1421	Fall River	Massachusetts	United States	02720
48	Forest Investigative Site 1029	North Dartmouth	Massachusetts	United States	02747
49	Forest Investigative Site 1405	Chelsea	Michigan	United States	48118
50	Forest Investigative Site 0889	Livonia	Michigan	United States	48152
51	Forest Investigative Site 1487	Troy	Michigan	United States	48085
52	Forest Investigative Site 1128	Edina	Minnesota	United States	58435
53	Forest Investigative Site 1527	Fridley	Minnesota	United States	55432
54	Forest Investigative Site 1124	Minneapolis	Minnesota	United States	55403
55	Forest Investigative Site 1118	Rochester	Minnesota	United States	55904
56	Forest Investigative Site 1399	St. Louis	Missouri	United States	63141
57	Forest Investigative Site 1400	Missoula	Montana	United States	59808
58	Forest Investigative Site 1354	Bellevue	Nebraska	United States	68005
59	Forest Investigative Site 1367	Bellevue	Nebraska	United States	68123
60	Forest Investigative Site 1476	Fremont	Nebraska	United States	68025
61	Forest Investigative Site 1363	Omaha	Nebraska	United States	68114
62	Forest Investigative Site 1390	Omaha	Nebraska	United States	68130
63	Forest Investigative Site 1422	Omaha	Nebraska	United States	68134
64	Forest Investigative Site 1359	Henderson	Nevada	United States	89014
65	Forest Investigative Site 1355	Las Vegas	Nevada	United States	89123
66	Forest Investigative Site 1486	Albuquerque	New Mexico	United States	87108
67	Forest Investigative Site 1489	Larchmont	New York	United States	10538
68	Forest Investigative Site 1425	New York	New York	United States	10028
69	Forest Investigative Site 1373	North Syracuse	New York	United States	13212
70	Forest Investigative Site 1392	Charlotte	North Carolina	United States	28277
71	Forest Investigative Site 1366	High Point	North Carolina	United States	27262
72	Forest Investigative Site 1136	Cincinnati	Ohio	United States	45227
73	Forest Investigative Site 1371	Cincinnati	Ohio	United States	45245
74	Forest Investigative Site 1361	Columbus	Ohio	United States	43209
75	Forest Investigative Site 1433	Columbus	Ohio	United States	43213
76	Forest Investigative Site 1530	Toledo	Ohio	United States	43608
77	Forest Investigative Site 1393	Zanesville	Ohio	United States	43701
78	Forest Investigative Site 1362	Oklahoma City	Oklahoma	United States	73112
79	Forest Investigative Site 2018	Medford	Oregon	United States	97504
80	Forest Investigative Site 2043	Medford	Oregon	United States	97504
81	Forest Investigative Site 1377	Collegeville	Pennsylvania	United States	19426
82	Forest Investigative Site 1423	Erie	Pennsylvania	United States	16508
83	Forest Investigative Site 1428	Feasterville	Pennsylvania	United States	19053
84	Forest Investigative Site 1443	Philadelphia	Pennsylvania	United States	19107
85	Forest Investigative Site 1510	Pittsburgh	Pennsylvania	United States	15221
86	Forest Investigative Site 1449	Tipton	Pennsylvania	United States	16684
87	Forest Investigative Site 1445	Johnston	Rhode Island	United States	02919
88	Forest Investigative Site 1477	Lincoln	Rhode Island	United States	02865
89	Forest Investigative Site 1144	Columbia	South Carolina	United States	29201
90	Forest Investigative Site 1517	Easley	South Carolina	United States	29640
91	Forest Investigative Site 1506	Grenville	South Carolina	United States	29615
92	Forest Investigative Site 1450	Union	South Carolina	United States	29379
93	Forest Investigative Site 1526	Fayetteville	Tennessee	United States	37337
94	Forest Investigative Site 1356	Knoxville	Tennessee	United States	37909
95	Forest Investigative Site 1417	Knoxville	Tennessee	United States	37920
96	Forest Investigative Site 1389	Amarillo	Texas	United States	79106
97	Forest Investigative Site 1440	Arlington	Texas	United States	76012
98	Forest Investigative Site 1494	Austin	Texas	United States	78756
99	Forest Investigative Site 1375	Houston	Texas	United States	77074
100	Forest Investigative Site 1444	Houston	Texas	United States	77079
101	Forest Investigative Site 1401	Houston	Texas	United States	77083
102	Forest Investigative Site 1381	Houston	Texas	United States	77479
103	Forest Investigative Site 1357	Hurst	Texas	United States	76054
104	Forest Investigative Site 1426	Plano	Texas	United States	75093
105	Forest Investigative Site 1410	Tomball	Texas	United States	77375
106	Forest Investigative Site 1480	Abingdon	Virginia	United States	24210
107	Forest Investigative Site 1402	Lynchburg	Virginia	United States	24501
108	Forest Investigative Site 1404	Norfolk	Virginia	United States	23502
109	Forest Investigative Site 1358	Richmond	Virginia	United States	23294
110	Forest Investigative Site 0988	Tacoma	Washington	United States	98405
111	Forest Investigative Site 1177	Vancouver	British Columbia	Canada	V5Z 4E1
112	Forest Investigative Site 0969	Windsor	Ontario	Canada	N8X 5A6

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Esther Garcia, Ph. D., AstraZeneca

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• las-md-38-synopsis

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01045161
• Other Study ID Numbers: LAS-MD-38
• First Posted: Jan 8, 2010
• Last Update Posted: Jan 23, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by AstraZeneca: Chronic Obstructive Pulmonary Disease; COPD; Chronic Bronchitis; Emphysema; Airflow Obstruction, Chronic; Chronic Airflow Obstruction; Chronic Obstructive Airway Disease; Chronic Obstructive Lung Disease
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Bromides

Study Results

Participant Flow

Recruitment Details	Patient recruitment occurred from December of 2009 to June of 2010 at 112 study sites (110 in the United States and 2 additional sites in Canada).
Pre-assignment Detail	A total of 544 patients were randomized, with 542 in the Part A Safety population. Of the 454 patients who completed Part A, 448 patients continued into Part B, receiving at least 1 dose of open-label treatment, were included in the Part B Safety Population. Of these patients, 405 had a baseline and postbaseline assessment for the ITT Population.

Arm/Group Title	Placebo - Part A Placebo to Aclidinium Bromide 400 μg - Part B	Aclidinium Bromide 200μg to Aclidinium Bromide 400μg	Aclidinium Bromide 400μg to Aclidinium Bromide 400μg
Arm/Group Description	Dose matched placebo, twice per day, oral inhalation for 12 weeks of double-blind treatment. After 12 weeks, patients who were on placebo received open-label Aclidinium Bromide, 400 microgram dose, for an additional 40 weeks.	Aclidinium bromide 200 microgram dose, oral inhalation, twice per day for 12 weeks of double-blind treatment. After 12 weeks, patients who were Aclidinium bromide 200 microgram dose, received open-label Aclidinium Bromide, 400 microgram dose, for an additional 40 weeks.	Aclidinium bromide, 400 microgram dose, oral inhalation twice per day for 12 weeks of double-blind treatment. After 12 weeks, patients continued to receive Aclidinium bromide, 400 microgram dose as an open-label treatment for an additional 40 weeks
Period Title: Part A - 12 Weeks Double Blind Treatment
STARTED	182	184	178
COMPLETED	151	155	148
NOT COMPLETED	31	29	30
Period Title: Part A - 12 Weeks Double Blind Treatment
STARTED	147	154	147
COMPLETED	111	118	115
NOT COMPLETED	36	36	32

Baseline Characteristics

Arm/Group Title	Placebo Part A / Placebo to Aclidinium Bromide 400μg Part B	Aclidinium Bromide(AB) 200μg Part A / AB 200μg to 400μg Part B	Aclidinium Bromide(AB) 400μg Part A / AB 400μg to 400μg Part B	Total
Arm/Group Description	Dose-matched placebo, twice per day, oral inhalation for 12 weeks of double-blind treatment in Part A of the Trial. After week 12 (conclusion of Part A), patients who were on placebo received open-label Aclidinium Bromide, 400 microgram dose, for an additional 40 weeks.	Aclidinium bromide 200 microgram dose, oral inhalation, twice per day for 12 weeks of double-blind treatment in Part A of the Trial. After week 12 (conclusion of Part A), patients who were on a double-blind, 200 microgram Aclidinium Bromide dose, were switched to open-label Aclidinium Bromide at a 400 microgram dose for an additional 40 weeks.	Aclidinium bromide, 400 microgram dose, oral inhalation twice per day for 12 weeks of double-blind treatment in Part A of the Trial. After week 12 (conclusion of Part A), patients who were on a double-blind, 400 microgram Aclidinium Bromide dose, were switched to open-label Aclidinium Bromide at the same 400 microgram dose for an additional 40 weeks.	Total of all reporting groups
Overall Participants	182	183	177	542
Age (years) [Mean (Standard Deviation) ]
Part A	61.7 (9.3)	63.4 (8.5)	63.2 (9.0)	62.8 (8.9)
Part B	61.3 (9.1)	63.8 (8.2)	63.1 (8.6)	62.8 (8.7)
Age, Customized (participants) [Number]
≥ 40 to < 60 years - Part A	72 39.6%	57 31.1%	57 32.2%	186 34.3%
≥ 60 to < 70 years - Part A	72 39.6%	79 43.2%	77 43.5%	228 42.1%
≥ 70 years - Part A	38 20.9%	47 25.7%	43 24.3%	128 23.6%
≥ 40 to < 60 years - Part B	60 33%	46 25.1%	46 26%	152 28%
≥ 60 to < 70 years - Part B	58 31.9%	67 36.6%	67 37.9%	192 35.4%
≥ 70 years - Part B	29 15.9%	41 22.4%	34 19.2%	104 19.2%
Gender (Count of Participants)
Female	82 45.1%	84 45.9%	88 49.7%	254 46.9%
Male	100 54.9%	99 54.1%	89 50.3%	288 53.1%
Gender (Count of Participants)
Female	82 45.1%	84 45.9%	88 49.7%	254 46.9%
Male	100 54.9%	99 54.1%	89 50.3%	288 53.1%
Region of Enrollment (participants) [Number]
United States	180 98.9%	181 98.9%	175 98.9%	536 98.9%
Canada	2 1.1%	2 1.1%	2 1.1%	6 1.1%
Region of Enrollment (participants) [Number]
United States	145 79.7%	152 83.1%	145 81.9%	442 81.5%
Canada	2 1.1%	2 1.1%	2 1.1%	6 1.1%

Outcome Measures

1. Primary Outcome

Title	Part A: Morning Predose (Trough) Forced Expiratory Volume in 1 Second (FEV1)
Description	Change from baseline in Trough forced expiratory volume in 1 second before the morning dose of aclidinium bromide, Last Observation Carried Forward (LOCF)
Time Frame	Change from baseline (Week 0) to Week 12

Outcome Measure Data

Analysis Population Description

Of 544 patients randomized, 542 patients received at least 1 dose of double-blind treatment and were included in the Safety Population. Of these patients, 541 had a baseline and at least 1 postbaseline FEV1 assessment and qualified for the Intent to Treat (ITT) Population.

Arm/Group Title	Placebo	Aclidinium Bromide 200 μg	Aclidinium Bromide 400 μg
Arm/Group Description	Dose-matched placebo twice per day, inhaled for 12 weeks of treatment.	Aclidinium bromide 200 μg dose twice per day, inhaled for 12 weeks of treatment.	Inhaled Aclidinium bromide 400 μg twice per day for 12 weeks.
Measure Participants	182	182	177
Least Squares Mean (Standard Error) [L]	-0.008 (0.015)	0.043 (0.015)	0.064 (0.016)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aclidinium Bromide 200 μg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.051
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aclidinium Bromide 400 μg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.072
	Confidence Interval	(2-Sided) 95%; 0.03 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Part A: Peak Forced Expiratory Volume in 1 Second (FEV1)
Description	Change from baseline in peak FEV1 at week 12, Last Observation Carried Forward (LOCF)
Time Frame	Change from baseline (Week 0) to Week 12

Outcome Measure Data

Analysis Population Description

Of 544 patients randomized, 542 patients received at least 1 dose of double-blind treatment and were included in the Safety Population. Of these patients, 541 had a baseline and at least 1 postbaseline FEV1 assessment and qualified for the Intent to Treat (ITT) Population.

Arm/Group Title	Placebo	Aclidinium Bromide 200 μg	Aclidinium Bromide 400 μg
Arm/Group Description	Dose-matched placebo twice per day, inhaled for 12 weeks of treatment.	Aclidinium bromide 200 μg dose twice per day, inhaled for 12 weeks of treatment.	Inhaled Aclidinium bromide 400 μg twice per day for 12 weeks.
Measure Participants	182	182	177
Least Squares Mean (Standard Error) [L]	0.087 (0.018)	0.202 (0.018)	0.212 (0.018)

3. Primary Outcome

Title	Part B: Morning Predose (Trough) FEV1
Description	Change from Baseline in Morning Pre-dose (trough) Forced Expiratory Volume in 1 Second (FEV1) at Week 52, Lost Observation Carried Forward (LOCF)
Time Frame	Change from baseline (Week 0) to 52 Weeks

Outcome Measure Data

Analysis Population Description

A total of 544 patients were randomized, with 542 in the Part A Safety population. Of the 454 patients who completed Part A, 448 patients continued into Part B, receiving at least 1 dose of open-label treatment, were included in the Part B Safety Population. Of these patients, 405 had a baseline and postbaseline assessment for the ITT Population.

Arm/Group Title	Placebo - Aclidinium Bromide 400 μg	Aclidinium Bromide 200 μg - Aclidinium Bromide 400 μg	Aclidinium Bromide 400 μg - Aclidinium Bromide 400 μg
Arm/Group Description	Dose matched placebo, oral inhalation, twice per day for 12 weeks of treatment. At week 12, patients who were on placebo were switched to open label 400µg aclidinium bromide for 40 weeks	Aclidinium bromide, 200 μg dose, oral inhalation, twice per day for 12 weeks of treatment. At week 12, patients who were on Aclidinium bromide 200 μg were switched to open label 400µg aclidinium bromide for 40 weeks.	Aclidinium bromide, 400 μg dose, oral inhalation, twice per day for 12 weeks of treatment. At week 12, patients received open label 400µg aclidinium bromide for 40 additional weeks
Measure Participants	134	139	132
Mean (Standard Deviation) [L]	0.045 (0.021)	0.029 (0.020)	0.048 (0.021)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aclidinium Bromide 200 μg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0192
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.051
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aclidinium Bromide 400 μg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean difference
	Estimated Value	0.072
	Confidence Interval	(2-Sided) 95%; 0.03 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Part B: Peak FEV1
Description	Change from Baseline in Peak FEV1 (L) at Week 52, Last Observation Carried Forward (LOCF)
Time Frame	Change from baseline (Week 0) to 52 Weeks

Outcome Measure Data

Analysis Population Description

A total of 544 patients were randomized, with 542 in the Part A Safety population. Of the 454 patients who completed Part A, 448 patients continued into Part B, receiving at least 1 dose of open-label treatment, were included in the Part B Safety Population. Of these patients, 405 had a baseline and postbaseline assessment for the ITT Population.

Arm/Group Title	Placebo - Aclidinium Bromide 400 μg	Aclidinium Bromide 200 μg - Aclidinium Bromide 400 μg	Aclidinium Bromide 400 μg - Aclidinium Bromide 400 μg
Arm/Group Description	Dose matched placebo, oral inhalation twice per day for 12 weeks. At week 12, patients who were on placebo switched to open label 400µg aclidinium bromide for 40 weeks	Aclidinium bromide 200 μg, oral inhalation twice per day for 12 weeks of treatment. At week 12, patients who were on Aclidinium bromide 200 μg switched to open label 400µg aclidinium bromide for 40 weeks	Aclidinium bromide 400 μg dose, oral inhalation twice per day for 12 weeks of treatment. At week 12, patients who were on Aclidinium bromide 400 μg switched to open label 400µg aclidinium bromide for 40 weeks
Measure Participants	134	139	132
Least Squares Mean (Standard Error) [L]	0.185 (0.023)	0.176 (0.023)	0.172 (0.023)

Adverse Events

Time Frame	Adverse Event reporting began in December of 2009 and concluded in July of 2011 at 112 study sites (110 in the United States and 2 additional sites in Canada).
Arm/Group Title	Placebo - Part A		Aclidinium Bromide 200 μg - Part A		Aclidinium Bromide 400 μg - Part A		Placebo to Aclidinium Bromide 400 μg - Part B		Aclidinium Bromide 200μg to Aclidinium Bromide 400μg - Part B		Aclidinium Bromide 400μg to Aclidinium Bromide 400μg - Part B
Arm/Group Description	Dose matched placebo, twice per day, oral inhalation for 12 weeks of double-blind treatment.		Aclidinium bromide 200 microgram dose, oral inhalation, twice per day for 12 weeks of double-blind treatment.		Aclidinium bromide, 400 microgram dose, oral inhalation twice per day for 12 weeks of double-blind treatment.		After week 12 (conclusion of Part A), patients who were on placebo received open-label Aclidinium Bromide, 400 microgram dose, for an additional 40 weeks.		Part B - After week 12 (conclusion of Part A), patients who were on a double-blind, 200 microgram Aclidinium Bromide dose, were switched to open-label Aclidinium Bromide at a 400 microgram dose for an additional 40 weeks.		After week 12 (conclusion of Part A), patients who were on a double-blind, 400 microgram Aclidinium Bromide dose, were switched to open-label Aclidinium Bromide at the same 400 microgram dose for an additional 40 weeks.
All Cause Mortality
	Placebo - Part A		Aclidinium Bromide 200 μg - Part A		Aclidinium Bromide 400 μg - Part A		Placebo to Aclidinium Bromide 400 μg - Part B		Aclidinium Bromide 200μg to Aclidinium Bromide 400μg - Part B		Aclidinium Bromide 400μg to Aclidinium Bromide 400μg - Part B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo - Part A		Aclidinium Bromide 200 μg - Part A		Aclidinium Bromide 400 μg - Part A		Placebo to Aclidinium Bromide 400 μg - Part B		Aclidinium Bromide 200μg to Aclidinium Bromide 400μg - Part B		Aclidinium Bromide 400μg to Aclidinium Bromide 400μg - Part B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/182 (6.6%)		11/183 (6%)		8/177 (4.5%)		15/147 (10.2%)		20/154 (13%)		14/147 (9.5%)
Blood and lymphatic system disorders
Anaemia	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		1/147 (0.7%)
Cardiac disorders
Coronary artery disease	0/182 (0%)		0/183 (0%)		0/177 (0%)		2/147 (1.4%)		2/154 (1.3%)		0/147 (0%)
Acute myocardial infarction	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		2/147 (1.4%)		0/154 (0%)		0/147 (0%)
Cardiac arrest	0/182 (0%)		0/183 (0%)		0/177 (0%)		1/147 (0.7%)		0/154 (0%)		1/147 (0.7%)
Cardiac failure congestive	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		2/154 (1.3%)		0/147 (0%)
Cardio-respiratory arrest	0/182 (0%)		0/183 (0%)		1/177 (0.6%)		1/147 (0.7%)		0/154 (0%)		0/147 (0%)
Myocardial ischaemia	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Angina pectoris	0/182 (0%)		2/183 (1.1%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Atrial fibrillation	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Ear and labyrinth disorders
Labyrinthitis	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Gastrointestinal disorders
Abdominal pain	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Pancreatitis	0/182 (0%)		0/183 (0%)		0/177 (0%)		1/147 (0.7%)		0/154 (0%)		0/147 (0%)
Gastrenteritis salmonella	0/182 (0%)		0/183 (0%)		1/177 (0.6%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Diarrhoea	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Duodenal ulcer	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Gastrointestinal haemorrhage	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
General disorders
Non-cardiac chest pain	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		1/147 (0.7%)		1/154 (0.6%)		0/147 (0%)
Chest pain	0/182 (0%)		0/183 (0%)		0/177 (0%)		1/147 (0.7%)		0/154 (0%)		0/147 (0%)
Death	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Hepatobiliary disorders
Cholangitis	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Cholecystitis acute	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Infections and infestations
Bronchitis	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Clostridium difficile colitis	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Diverticulitis	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Influenza	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Lobar pneumonia	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Osteomyelitis	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Osteomyelitis bacterial	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Staphylococcal bacteraemia	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Staphylococcal sepsis	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Staphylococcal skin infection	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Lobar pneumonia	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Injury, poisoning and procedural complications
Cervical vertebral fracture	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Femoral neck fracture	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Haematoma	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Fall	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Joint injury	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/182 (0%)		0/183 (0%)		0/177 (0%)		1/147 (0.7%)		0/154 (0%)		0/147 (0%)
Dehydration	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Breast cancer	0/182 (0%)		0/183 (0%)		0/177 (0%)		1/147 (0.7%)		0/154 (0%)		0/147 (0%)
Laryngeal cancer	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Renal cell carcinoma	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Nervous system disorders
Cerebrovascular accident	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		1/147 (0.7%)
Carotid artery stenosis	0/182 (0%)		0/183 (0%)		0/177 (0%)		1/147 (0.7%)		0/154 (0%)		0/147 (0%)
Lumbar radiculopathy	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Migraine	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Subarachnoid haemorrhage	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
VIIth nerve paralysis	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Psychiatric disorders
Mental status changes	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Agitated depression	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Suicidal ideation	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Renal and urinary disorders
Renal failure acute	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Reproductive system and breast disorders
Cystocele	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Uterine haemorrhage	0/182 (0%)		0/183 (0%)		0/177 (0%)		1/147 (0.7%)		0/154 (0%)		0/147 (0%)
Vulvar dysplasia	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Benign prostatic hyperplasia	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	6/182 (3.3%)		5/183 (2.7%)		5/177 (2.8%)		4/147 (2.7%)		7/154 (4.5%)		3/147 (2%)
Pneumonia	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		1/147 (0.7%)		1/154 (0.6%)		0/147 (0%)
Acute respiratory failure	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Dyspnoea	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Pneumonitis	0/182 (0%)		0/183 (0%)		0/177 (0%)		1/147 (0.7%)		0/154 (0%)		0/147 (0%)
Pulmonary embolism	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Pulmonary mass	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Pulmonary oedema	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		1/154 (0.6%)		0/147 (0%)
Pseudomonas bronchitis	0/182 (0%)		0/183 (0%)		1/177 (0.6%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Lung adenocarcinoma	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Pneumothorax	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Respiratory acidosis	1/182 (0.5%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Vascular disorders
Hypotension	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Peripheral arterial occlusive disease	0/182 (0%)		0/183 (0%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		1/147 (0.7%)
Aortic aneurysm	0/182 (0%)		0/183 (0%)		1/177 (0.6%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Transient ischaemic attack	0/182 (0%)		1/183 (0.5%)		0/177 (0%)		0/147 (0%)		0/154 (0%)		0/147 (0%)
Other (Not Including Serious) Adverse Events
	Placebo - Part A		Aclidinium Bromide 200 μg - Part A		Aclidinium Bromide 400 μg - Part A		Placebo to Aclidinium Bromide 400 μg - Part B		Aclidinium Bromide 200μg to Aclidinium Bromide 400μg - Part B		Aclidinium Bromide 400μg to Aclidinium Bromide 400μg - Part B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/182 (12.1%)		20/183 (10.9%)		28/177 (15.8%)		37/147 (25.2%)		50/154 (32.5%)		52/147 (35.4%)
Infections and infestations
Upper respiratory tract infection	1/182 (0.5%)		3/183 (1.6%)		3/177 (1.7%)		9/147 (6.1%)		9/154 (5.8%)		8/147 (5.4%)
Respiratory, thoracic and mediastinal disorders
COPD exacerbation	21/182 (11.5%)		16/183 (8.7%)		23/177 (13%)		24/147 (16.3%)		35/154 (22.7%)		41/147 (27.9%)
Nasopharyngitis	0/182 (0%)		2/183 (1.1%)		2/177 (1.1%)		6/147 (4.1%)		9/154 (5.8%)		6/147 (4.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All data generated in this study will be the property of Forest Research Institute, Inc. An integrated clinical and statistical report will be prepared at the completion of the study. Publication of the results by the Investigator will be subject to mutual agreement between the Investigator and Forest Research Institute, Inc.