Efficacy, Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Compared With Aclidinium Bromide and Formoterol Fumarate in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01437397
• Collaborator: (none)
• Enrollment: 1,692
• Locations: 222
• Arms: 5
• Duration (Months): 17.1
• Patients Per Site: 7.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this Phase III study is to assess the maintenance bronchodilator effects of the fixed dose combination versus monotherapies. This study will also assess the effects of the fixed dose combination in terms of COPD symptoms, disease related health status and the long-term safety and tolerability of the fixed dose combination. This study will include a 24 week treatment period, preceding by a run-in period, followed by a two week follow up visit. All patients will be randomized to one of four treatment arms or placebo.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 1692 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-blind, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Tolerability of Two Fixed Dose Combinations of Aclidinium Bromide/Formoterol Fumarate Compared With Aclidinium Bromide, Formoterol Fumarate and Placebo for 24- Weeks Treatment in Patients With Moderate to Severe, Stable Chronic Obstructive Pulmonary Disease (COPD).
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Aclidinium/formoterol Fixed Dose Combination (FDC) 400/12μg	Drug: Aclidinium Bromide/Formoterol Fumarate; Inhaled Aclidinium/formoterol FDC 400/12μg, twice per day
Experimental: 2 Aclidinium/formoterol Fixed Dose Combination (FDC) 400/6μg	Drug: Aclidinium Bromide/Formoterol Fumarate; Inhaled Aclidinium/formoterol FDC 400/6μg, twice per day
Active Comparator: 3 Aclidinium monotherapy 400 μg	Drug: Aclidinium Bromide; Inhaled Aclidinium 400 μg, twice per day
Active Comparator: 4 Formoterol monotherapy 12 μg	Drug: Formoterol Fumarate; Inhaled Formoterol 12 μg, twice per day
Placebo Comparator: 5 Placebo	Drug: Placebo; Inhaled dose-matched placebo, twice per day

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1) [Week 24 of treatment]

2. Change From Baseline in Morning Trough Forced Expiratory Volume in One Second (FEV1) [Week 24 of treatment]

Secondary Outcome Measures

1. Change in Transition Dyspnea Index (TDI) Focal Score [Week 24 of treatment]

   The TDI measures the change from baseline in severity of breathlessness in symptomatic patients. The TDI contains a rating for 3 categories (functional impairment, magnitude of task, magnitude of effort).TDI scale ranges from -3 (major deterioration) to +3 (major improvement) including a 0 score to indicate "no change". The 3 categories are added to obtain a focal score ranging from -9 (including 0) to +9.

2. Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score [Week 24 of treatment]

   St George's Respiratory Questionnaire (SGRQ) measures COPD-specific health outcomes and consists of 2 parts with 3 dimension scores (a symptom score and an activity and impacts score). SGRQ total score is the sum of these scores and ranges from 0 (best health status) to 100 (worst health status).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female patients at least 40 years of age

• Current or former cigarette smoker with a cigarette smoking history of at least 10 pack-years

• A diagnosis of stable moderate to severe COPD and stable airway obstruction as defined by the GOLD guidelines and stable airway obstruction. Patients had to have a postbronchodilator FEV1/FVC ratio < 70% at Visit 1 (GOLD, 2010)

• Post-albuterol/salbutamol FEV1 values ≥ 30% and < 80% of predicted value. FEV1 was measured at the Screening Visit (Visit 1) 10 to 15 minutes after inhalation of albuterol/salbutamol. Predicted normal used for calculation purposes were based on National Health and Nutrition Examination Survey III predicted values (Hankinson et al, 1999)

• Able to perform acceptable and repeatable pulmonary function testing for FEV1 according to ATS/ERS criteria (Miller et al, 2005) at Screening Visit (Visit 1) and throughout their participation in the trial

• Negative serum β-human chorionic gonadotropin pregnancy test at Visit 1 and must have been using hormonal contraceptives or a barrier method plus a spermicidal agent; otherwise at least 1-year postmenopausal or surgically sterile, defined as having a hysterectomy or tubal ligation (applied to female patients only)

• Judged by the Principal Investigator to be in otherwise good stable health based on medical history, physical examination, ECGs, and routine laboratory data evaluations

• Patients previously randomized in an aclidinium monotherapy trial were permitted as long as it had been at least 6 months since the completion of their previous trial participation

• Able to understand the study procedures and be willing to participate in the study as indicated by signing the informed consent

Exclusion Criteria:

• Hospitalization for an acute COPD exacerbation within 3 months before Visit 1

• Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the 6 weeks before Visit 1. Patients who developed a respiratory tract infection or COPD exacerbation during the washout or run-in period were discontinued from the study before randomization

• Any clinically significant respiratory conditions other than COPD, including active tuberculosis, history of interstitial lung disease, pulmonary thromboembolic disease, history of α1-antitrypsin deficiency, pulmonary resection, lung volume surgery, or any other thoracic surgery during the past 12 months, history of bronchiectasis secondary to respiratory diseases other than COPD (eg, cystic fibrosis, Kartagener syndrome), post organ transplantation, or expected to require thoracotomy or other lung surgery during the study

• Clinical history suggesting that the patient had asthma as opposed to COPD (Study Physician was to be contacted to discuss eligibility, if necessary)

• Chronic use of oxygen therapy ≥ 15 hours/day

• Body mass index(BMI) ≥ 40 kg/m2

• Patients who intended to start a pulmonary rehabilitation program during the trial were excluded, as well as those who finished or started it within 3 months prior to Screening Visit

• Clinically significant cardiovascular conditions including: myocardial infarction within 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 within the previous 6 months; the presence of an automated implantable cardioverter-defibrillator; history of thoracic surgery within the past year before screening; hospitalization within the previous 12 months for heart failure of New York Heart Association functional class III (marked limitation of physical activity and only comfortable at rest, less than ordinary activity causes fatigue, palpitation or dyspnea), or class IV (unable to carry out any physical activity without discomfort) (Criteria Committee of the New York Heart Association criteria, 1994)

• Any uncontrolled infection that may have placed the patient at risk resulting from human immunodeficiency virus, active hepatitis and/or patients with diagnosed active tuberculosis

• QTcB > 470 msec in the resting ECGs performed at Screening (Visit 1), as indicated in the centralized ECG vendor generated report. Patients who were on a stable dose of medication that may prolong the QTc, but had a documented, stable, and normal QTc, could have been considered

• QTcB > 470 msec in the resting ECGs performed before randomization at Visit 2, as indicated in the paper tracing generated by the Sponsor-provided ECG equipment

• Clinically relevant abnormalities in the results of the clinical laboratory tests, in ECG parameters other than QTc, or in the physical examination or vital signs at Visit 1 except for those related to COPD

• History of drug or alcohol abuse within the previous 5 years

• Any other serious or uncontrolled physical or mental condition/disease that, as judged by the Investigator, could have placed the patient at higher risk derived from his/her participation in the study, could have confounded the results of the study, or would be likely to have prevented the patient from complying with the requirements of the study or completing the study. If there was a history of such disease, but the condition had been stable for more than 1 year and was judged by the Investigator not to interfere with the patient's participation in the study, the patient may have been included, with the documented approval of the Study Physician

• History of hypersensitivity reaction to inhaled anticholinergics, beta-2 agonists, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm) or a history of acute urinary retention, symptomatic benign prostatic hyperplasia, bladder neck obstruction, or narrow-angle glaucoma. (Note: Patients who had well controlled, stable, asymptomatic benign prostatic hyperplasia were not to be excluded)

• Sitting, resting systolic BP ≥ 160 mm Hg and/or diastolic BP ≥ 100 mm Hg at Visit 1 and Visit 2

• Unable to use a multidose dry-powder inhaler or a pressurized metered-dose inhaler

• Treatment with any other investigational product within 30 days (or 6 half-lives, whichever was longer) before Visit 1

• Previous participation in a clinical trial with aclidinium bromide in an FDC therapy

• Pregnant or breastfeeding

• Current diagnosis of cancer (present in the patient) other than basal or squamous cell skin cancer. Patients who had a history of cancer must have been cleared before Visit 1 (Screening) on a case-by-case basis

• Patients who did not maintain regular day/night, waking/sleeping cycles (eg, night shift workers)

• Patients who intended to use any concomitant medication not permitted by this protocol or who had not undergone the required washout period for a particular prohibited medication (Appendix III of the protocol, which can be found in Appendix 16.1.1 of this report)

• Patients who were unlikely to be compliant with study requirements (eg, take their medication, complete their electronic diaries, attend clinic at the required times)

• Patients who were employees or relatives of employees of the investigative study center, FRI, Almirall, SA, or Pharmaceutical Product Development (PPD, Inc.)

• Patients who had any other conditions that, in the Investigator's opinion, might have indicated the patient to be unsuitable for the study or supported excluding the patient from the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site 1827	Anniston	Alabama	United States	36207
2	Forest Investigative Site 1920	Athens	Alabama	United States	35611
3	Forest Investigative Site 1162	Birmingham	Alabama	United States	35209
4	Forest Investigative Site 1493	Birmingham	Alabama	United States	35209
5	Forest Investigative Site 1937	Birmingham	Alabama	United States	35216
6	Forest Investigative Site 1893	Florence	Alabama	United States	35630
7	Forest Investigative Site 1824	Gulf Shores	Alabama	United States	36542
8	Forest Investigative Site 2088	Jasper	Alabama	United States	35501
9	Forest Investigative Site 1918	Scottsboro	Alabama	United States	35768
10	Forest Investigative Site 0909	Glendale	Arizona	United States	85306
11	Forest Investigative Site 1958	Mesa	Arizona	United States	85206
12	Forest Investigative Site 1379	Phoenix	Arizona	United States	85018
13	Forest Investigative Site 1822	Anaheim	California	United States	92801
14	Forest Investigative Site 1483	Buena Park	California	United States	90620
15	Forest Investigative Site 1809	Fountain Valley	California	United States	92708
16	Forest Investigative Site 1156	Fresno	California	United States	93726
17	Forest Investigative Site 1871	Lincoln	California	United States	95648
18	Forest Investigative Site 1873	Los Angeles	California	United States	90073
19	Forest Investigative Site 2064	Riverside	California	United States	92506
20	Forest Investigative Site 1427	Sacramento	California	United States	95817
21	Forest Investigative Site 1866	Sacramento	California	United States	95842
22	Forest Investigative Site 1125	San Diego	California	United States	92103
23	Forest Investigative Site 1898	San Diego	California	United States	92111
24	Forest Investigative Site 2009	San Diego	California	United States	92120
25	Forest Investigative Site 1374	Torrance	California	United States	90505
26	Forest Investigative Site 1813	Tustin	California	United States	92780
27	Forest Investigative Site 1883	Vista	California	United States	92083
28	Forest Investigative Site 1380	Golden	Colorado	United States	80401
29	Forest Investigative Site 1137	Pueblo	Colorado	United States	81001
30	Forest Investigative Site 1327	Wheat Ridge	Colorado	United States	80033
31	Forest Investigative Site 1976	Waterbury	Connecticut	United States	06708
32	Forest Investigative Site 1821	Bay Pines	Florida	United States	33744
33	Forest Investigative Site 1154	Brandon	Florida	United States	33511
34	Forest Investigative Site 1944	Brandon	Florida	United States	33511
35	Forest Investigative Site 1364	Clearwater	Florida	United States	33756
36	Forest Investigative Site 1152	Clearwater	Florida	United States	33765
37	Forest Investigative Site 1875	Clearwater	Florida	United States	33765
38	Forest Investigative Site 0670	DeLand	Florida	United States	32720
39	Forest Investigative Site 1516	Edgewater	Florida	United States	32132
40	Forest Investigative Site 0990	Fort Lauderdale	Florida	United States	33316
41	Forest Investigative Site 1513	Hialeah	Florida	United States	33012
42	Forest Investigative Site 1854	Hialeah	Florida	United States	33012
43	Forest Investigative Site 1882	Hollywood	Florida	United States	33024
44	Forest Investigative Site 1543	Jacksonville	Florida	United States	32216
45	Forest Investigative Site 1416	Kissimmee	Florida	United States	34741
46	Forest Investigative Site 1167	Melbourne	Florida	United States	32935
47	Forest Investigative Site 1868	Miami	Florida	United States	33135
48	Forest Investigative Site 1432	Miami	Florida	United States	33143
49	Forest Investigative Site 1979	Miami	Florida	United States	33144
50	Forest Investigative Site 1819	Naples	Florida	United States	34119
51	Forest Investigative Site 1808	North Miami Beach	Florida	United States	33179
52	Forest Investigative Site 1950	Oldsmar	Florida	United States	34677
53	Forest Investigative Site 1145	Ormond Beach	Florida	United States	32174
54	Forest Investigative Site 1094	Panama City	Florida	United States	32405
55	Forest Investigative Site 1803	Pembroke Pines	Florida	United States	33028
56	Forest Investigative Site 974	Pensacola	Florida	United States	32504
57	Forest Investigative Site 1876	Saint Petersburg	Florida	United States	33701
58	Forest Investigative Site 1817	Sarasota	Florida	United States	34233
59	Forest Investigative Site 1829	St. Cloud	Florida	United States	34769
60	Forest Investigative Site 1874	St. Petersburg	Florida	United States	33704
61	Forest Investigative Site 2082	Tamarac	Florida	United States	33321
62	Forest Investigative Site 2053	Tampa	Florida	United States	33603
63	Forest Investigative Site 2047	Tampa	Florida	United States	33613
64	Forest Investigative Site 1185	Winter Park	Florida	United States	32789
65	Forest Investigative Site 1860	Winter Park	Florida	United States	32792
66	Forest Investigative Site 1982	Albany	Georgia	United States	31707
67	Forest Investigative Site 1900	Atlanta	Georgia	United States	30312
68	Forest Investigative Site 0987	Austell	Georgia	United States	30106
69	Forest Investigative Site 1828	Canton	Georgia	United States	30114
70	Forest Investigative Site 1830	Marietta	Georgia	United States	30066
71	Forest Investigative Site 2089	Woodstock	Georgia	United States	30189
72	Forest Investigative Site 0679	Coeur d' Alene	Idaho	United States	83814
73	Forest Investigative Site 1858	Eagle	Idaho	United States	83616
74	Forest Investigative Site 1095	Normal	Illinois	United States	61761
75	Forest Investigative Site 1912	Normal	Illinois	United States	61761
76	Forest Investigative Site 2051	River Forest	Illinois	United States	60305
77	Forest Investigative Site 2033	Bowling Green	Kentucky	United States	42101
78	Forest Investigative Site 2085	Fort Mitchell	Kentucky	United States	41017
79	Forest Investigative Site 0539	Lexington	Kentucky	United States	40504
80	Forest Investigative Site 1478	Louisville	Kentucky	United States	40217
81	Forest Investigative Site 1519	Owensboro	Kentucky	United States	42303
82	Forest Investigative Site 1811	Covington	Louisiana	United States	70433
83	Forest Investigative Site 1430	New Orleans	Louisiana	United States	70115
84	Forest Investigative Site 1812	Opelousas	Louisiana	United States	70570
85	Forest Investigative Site 1814	Bangor	Maine	United States	04401
86	Forest Investigative Site 1924	Baltimore	Maryland	United States	21237
87	Forest Investigative Site 1865	Hollywood	Maryland	United States	20636
88	Forest Investigative Site 1872	Wheaton	Maryland	United States	20902
89	Forest Investigative Site 1570	Fall River	Massachusetts	United States	02720
90	Forest Investigative Site 1852	Fall river	Massachusetts	United States	02720
91	Forest Investigative Site 1029	North Dartmouth	Massachusetts	United States	02747
92	Forest Investigative Site 1431	North Dartmouth	Massachusetts	United States	02747
93	Forest Investigative Site 1892	Ann Arbor	Michigan	United States	48106
94	Forest Investigative Site 1342	Stevensville	Michigan	United States	49127
95	Forest Investigative Site 1487	Troy	Michigan	United States	48085
96	Forest Investigative Site 1128	Edina	Minnesota	United States	55435
97	Forest Investigative Site 1527	Fridley	Minnesota	United States	55432
98	Forest Investigative Site 2041	Minneapolis	Minnesota	United States	55402
99	Forest Investigative Site 1124	Minneapolis	Minnesota	United States	55407
100	Forest Investigative Site 1619	Plymouth	Minnesota	United States	55441
101	Forest Investigative Site 1118	Rochester	Minnesota	United States	55905
102	Forest Investigative Site 1884	Olive Branch	Mississippi	United States	38654
103	Forest Investigative Site 1587	Chesterfield	Missouri	United States	63017
104	Forest Investigative Site 1602	Kansas City	Missouri	United States	64128
105	Forest Investigative Site 1856	Springfield	Missouri	United States	65803
106	Forest Investigative Site 1867	Springfield	Missouri	United States	65807
107	Forest Investigative Site 2079	St. Charles	Missouri	United States	63301
108	Forest Investigative Site 1399	St. Louis	Missouri	United States	63141
109	Forest Investigative Site 1599	St. Louis	Missouri	United States	63141
110	Forest Investigative Site 1831	Bozeman	Montana	United States	59718
111	Forest Investigative Site 1400	Missoula	Montana	United States	59808
112	Forest Investigative Site 1609	Bellevue	Nebraska	United States	68123
113	Forest Investigative Site 1948	Fremont	Nebraska	United States	68025
114	Forest Investigative Site 1815	Lincoln	Nebraska	United States	68510
115	Forest Investigative Site 1363	Omaha	Nebraska	United States	68114
116	Forest Investigative Site 1907	Omaha	Nebraska	United States	68130
117	Forest Investigative Site 1911	Omaha	Nebraska	United States	68131
118	Forest Investigative Site 1908	Omaha	Nebraska	United States	68134
119	Forest Investigative Site 1804	Omaha	Nebraska	United States	68144
120	Forest Investigative Site 1807	Henderson	Nevada	United States	89052
121	Forest Investigative Site 1834	Las Vegas	Nevada	United States	89128
122	Forest Investigative Site 1562	Las Vegas	Nevada	United States	89183
123	Forest Investigative Site 1559	Cherry Hill	New Jersey	United States	08003
124	Forest Investigative Site 1923	Hackensack	New Jersey	United States	07601
125	Forest Investigative Site 1949	Albuquerque	New Mexico	United States	87106
126	Forest Investigative Site 1151	Great Neck	New York	United States	11021
127	Forest Investigative Site 1489	Larchmont	New York	United States	10538
128	Forest Investigative Site 0550	New York	New York	United States	10003
129	Forest Investigative Site 1425	New York	New York	United States	10028
130	Forest Investigative Site 2098	Rochester	New York	United States	14618
131	Forest Investigative Site 1392	Charlotte	North Carolina	United States	28277
132	Forest Investigative Site 2035	Elizabeth City	North Carolina	United States	27909
133	Forest Investigative Site 1366	High Point	North Carolina	United States	27262
134	Forest Investigative Site 1153	Raleigh	North Carolina	United States	27607
135	Forest Investigative Site 1823	Salisbury	North Carolina	United States	28144
136	Forest Investigative Site 1891	Cadiz	Ohio	United States	43907
137	Forest Investigative Site 1134	Canton	Ohio	United States	44718
138	Forest Investigative Site 1885	Cincinnati	Ohio	United States	45219
139	Forest Investigative Site 1806	Cincinnati	Ohio	United States	45231
140	Forest Investigative Site 2028	Cincinnati	Ohio	United States	45242
141	Forest Investigative Site 1903	Cincinnati	Ohio	United States	45245
142	Forest Investigative Site 1361	Columbus	Ohio	United States	43207
143	Forest Investigative Site 1433	Columbus	Ohio	United States	43213
144	Forest Investigative Site 2090	Sylvania	Ohio	United States	43560
145	Forest Investigative Site 1530	Toledo	Ohio	United States	43608
146	Forest Investigative Site 1393	Zanesville	Ohio	United States	43701
147	Forest Investigative Site 1915	Oklahoma City	Oklahoma	United States	73103
148	Forest Investigative Site 1889	Bend	Oregon	United States	97701
149	Forest Investigative Site 2043	Medford	Oregon	United States	97504
150	Forest Investigative Site 1833	Altoona	Pennsylvania	United States	16601
151	Forest Investigative Site 1855	Clairton	Pennsylvania	United States	15025
152	Forest Investigative Site 1820	Downington	Pennsylvania	United States	19335
153	Forest Investigative Site 1423	Erie	Pennsylvania	United States	16508
154	Forest Investigative Site 1899	Langhorne	Pennsylvania	United States	19047
155	Forest Investigative Site 1443	Philadelphia	Pennsylvania	United States	19107
156	Forest Investigative Site 1863	Phoenixville	Pennsylvania	United States	19460
157	Forest Investigative Site 1146	Pittsburgh	Pennsylvania	United States	15243
158	Forest Investigative Site 1449	Tipton	Pennsylvania	United States	16684
159	Forest Investigative Site 1862	Uniontown	Pennsylvania	United States	15473
160	Forest Investigative Site 1832	Cumberland	Rhode Island	United States	02864
161	Forest Investigative Site 1089	East Providence	Rhode Island	United States	02914
162	Forest Investigative Site 2072	Charleston	South Carolina	United States	29406
163	Forest Investigative Site 1905	Charleston	South Carolina	United States	29407
164	Forest Investigative Site 1802	Charleston	South Carolina	United States	29412
165	Forest Investigative Site 1914	Fort Mill	South Carolina	United States	29707
166	Forest Investigative Site 1913	Gaffney	South Carolina	United States	29340
167	Forest Investigative Site 1121	Spartanburg	South Carolina	United States	29303
168	Forest Investigative Site 1957	Brentwood	Tennessee	United States	37027
169	Forest Investigative Site 1526	Fayetteville	Tennessee	United States	37334
170	Forest Investigative Site 1440	Arlington	Texas	United States	76012
171	Forest Investigative Site 1879	Boerne	Texas	United States	78006
172	Forest Investigative Site 1861	Carrollton	Texas	United States	75007
173	Forest Investigative Site 1816	Corsicana	Texas	United States	75110
174	Forest Investigative Site 1890	Dallas	Texas	United States	75220
175	Forest Investigative Site 1332	El Paso	Texas	United States	79903
176	Forest Investigative Site 2012	Fort Worth	Texas	United States	76104
177	Forest Investigative Site 1951	Houston	Texas	United States	77070
178	Forest Investigative Site 1902	Killeen	Texas	United States	76543
179	Forest Investigative Site 1091	Mckinney	Texas	United States	75069
180	Forest Investigative Site 1826	Plano	Texas	United States	75001
181	Forest Investigative Site 0526	San Angelo	Texas	United States	76904
182	Forest Investigative Site 1895	San Antonio	Texas	United States	78212
183	Forest Investigative Site 1936	Salt Lake City	Utah	United States	84102
184	Forest Investigative Site 1330	South Burlington	Vermont	United States	25403
185	Forest Investigative Site 1945	Newport News	Virginia	United States	23606
186	Forest Investigative Site 1404	Norfolk	Virginia	United States	23502
187	Forest Investigative Site 1120	Bellingham	Washington	United States	98225
188	Forest Investigative Site 1977	Spokane	Washington	United States	99202
189	Forest Investigative Site 1878	Spokane	Washington	United States	99204
190	Forest Investigative Site 1573	Spokane	Washington	United States	99216
191	Forest Investigative Site 0988	Tacoma	Washington	United States	98405
192	Forest Investigative Site 1870	Tacoma	Washington	United States	98405
193	Forest Investigative Site 1555	Morgantown	West Virginia	United States	26505
194	Forest Investigative Site 1991	New Lambton	New South Wales	Australia	2305
195	Forest Investigative Site 1987	Redcliffe	Queensland	Australia	4020
196	Forest Investigative Site 1973	Woolloongabba	Queensland	Australia	4102
197	Forest Investigative Site 1981	Bedford Park	South Australia	Australia	5042
198	Forest Investigative Site 1990	Daw Park	South Australia	Australia	5041
199	Forest Investigative Site 2251	Toorak Gardens	South Australia	Australia	5065
200	Forest Investigative Site 2250	Clayton	Victoria	Australia	3168
201	Forest Investigative Site 1972	Fitzroy	Victoria	Australia	3011
202	Forest Investigative Site 1986	Geelong	Victoria	Australia	3220
203	Forest Investigative Site 1985	Parkville	Victoria	Australia	3050
204	Forest Investigative Site 2253	Adelaide	Western Australia	Australia	5000
205	Forest Investigative Site 1904	Langley	British Columbia	Canada	V3A 4H9
206	Forest Investigative Site 0905	Vancouver	British Columbia	Canada	V5Z 1M9
207	Forest Investigative Site 0976	Winnipeg	Manitoba	Canada	R2K 3S8
208	Forest Investigative Site 1877	Sarina	Ontario	Canada	N7T 4X3
209	Forest Investigative Site 1896	Sarnia	Ontario	Canada	N7T 4X3
210	Forest Investigative Site 1171	Toronto	Ontario	Canada	M5T 3A9
211	Forest Investigative Site 2203	Toronto	Ontario	Canada	M6H 3M2
212	Forest Investigative Site 1952	Montreal	Quebec	Canada	H2R 1V6
213	Forest Investigative Site 0943	Saskatoon	Saskatchewan	Canada	S7N0W8
214	Forest Investigative Site 1859	Quebec		Canada	G1V 4M6
215	Forest Investigative Site 1027	Auckland		New Zealand	1051
216	Forest Investigative Site 1970	Christchurch		New Zealand	8011
217	Forest Investigative Site 1967	Dunedin		New Zealand	9012
218	Forest Investigative Site 1964	Dunedin		New Zealand	9058
219	Forest Investigative Site 1968	Hamilton		New Zealand	3240
220	Forest Investigative Site 1965	Tauranga		New Zealand	3110
221	Forest Investigative Site 1980	Tauranga		New Zealand	3112
222	Forest Investigative Site 1025	Wellington		New Zealand	7366

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Esther Garcia, MD, AstraZeneca

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• CSR Synopsis

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01437397
• Other Study ID Numbers: LAC-MD-31
• First Posted: Sep 20, 2011
• Last Update Posted: Mar 23, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by AstraZeneca: COPD; Chronic Obstructive Pulmonary Disease; 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; Formoterol Fumarate

Study Results

Participant Flow

Recruitment Details	This study was conducted at 205 sites, 178 in the United States, 9 in Canada, 10 in Australia, and 8 in New Zealand. The first patient was screened in October 2011 and the last patient visit was in February 2013
Pre-assignment Detail	A total of 3260 patients were screened for eligibility; 1692 patients were randomized to treatment. A total of 1568 (48.1%) patients screen failed and were discontinued prior to randomization. The primary reason for screening failures was not meeting inclusion/exclusion criteria (41.6%)

Arm/Group Title	Aclidinium/Formoterol 400/12 μg	Aclidinium/Formoterol 400/6 μg	Aclidinium 400 μg	Formoterol 12 μg	Placebo
Arm/Group Description	Fixed-dose combination (FDC) administered BID by inhalation	Fixed-dose combination (FDC) administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation
Period Title: Overall Study
STARTED	338	338	340	339	337
COMPLETED	272	276	268	270	236
NOT COMPLETED	66	62	72	69	101

Baseline Characteristics

Arm/Group Title	Aclidinium/Formoterol 400/12 μg	Aclidinium/Formoterol 400/6 μg	Aclidinium 400 μg	Formoterol 12 μg	Placebo	Total
Arm/Group Description	Fixed-dose combination (FDC) administered BID by inhalation	Fixed-dose combination (FDC) administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation	Total of all reporting groups
Overall Participants	335	333	337	332	332	1669
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.2 (8.9)	63.9 (9.2)	64.4 (8.7)	63.7 (8.7)	63.5 (8.9)	63.9 (8.9)
Sex: Female, Male (Count of Participants)
Female	167 49.9%	146 43.8%	149 44.2%	163 49.1%	157 47.3%	782 46.9%
Male	168 50.1%	187 56.2%	188 55.8%	169 50.9%	175 52.7%	887 53.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1)
Time Frame	Week 24 of treatment

Outcome Measure Data

Analysis Population Description

ITT Population defined as all randomized patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment

Arm/Group Title	Aclidinium/Formoterol 400/12 μg	Aclidinium/Formoterol 400/6 μg	Aclidinium 400 μg	Formoterol 12 μg	Placebo
Arm/Group Description	Fixed-dose combination (FDC) administered BID by inhalation	Fixed-dose combination (FDC) administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation
Measure Participants	335	333	337	332	331
Least Squares Mean (Standard Error) [Liters]	0.247 (0.013)	0.226 (0.013)	0.139 (0.013)	0.165 (0.013)	-0.037 (0.014)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aclidinium/Formoterol 400/12 μg, Aclidinium 400 μg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Treatment, sex, smoking-status, visit and group-by-visit as factors; screening pre- and post-bronchodilator FEV1, age and baseline FEV1 as covariates
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.108
	Confidence Interval	(2-Sided) 95%; 0.073 to 0.144
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aclidinium/Formoterol 400/6 μg, Aclidinium 400 μg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Treatment, sex, smoking-status, visit and group-by-visit as factors; screening pre- and post-bronchodilator FEV1, age and baseline FEV1 as covariates
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.087
	Confidence Interval	(2-Sided) 95%; 0.052 to 0.123
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in Morning Trough Forced Expiratory Volume in One Second (FEV1)
Time Frame	Week 24 of treatment

Outcome Measure Data

Analysis Population Description

ITT Population defined as all randomized patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment

Arm/Group Title	Aclidinium/Formoterol 400/12 μg	Aclidinium/Formoterol 400/6 μg	Aclidinium 400 μg	Formoterol 12 μg	Placebo
Arm/Group Description	Fixed-dose combination (FDC) administered BID by inhalation	Fixed-dose combination (FDC) administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation
Measure Participants	335	333	337	332	331
Least Squares Mean (Standard Error) [Liters]	0.095 (0.012)	0.076 (0.012)	0.066 (0.012)	0.050 (0.012)	-0.035 (0.013)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aclidinium/Formoterol 400/12 μg, Formoterol 12 μg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Mixed Models Analysis
	Comments	Treatment, sex, smoking-status, visit and group-by-visit as factors; screening pre- and post-bronchodilator FEV1, age and baseline FEV1 as covariates
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.045
	Confidence Interval	(2-Sided) 95%; 0.011 to 0.079
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aclidinium/Formoterol 400/6 μg, Formoterol 12 μg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.133
	Comments
	Method	Mixed Models Analysis
	Comments	Treatment, sex, smoking-status, visit and group-by-visit as factors; screening pre- and post-bronchodilator FEV1, age and baseline FEV1 as covariates
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.026
	Confidence Interval	(2-Sided) 95%; -0.008 to 0.060
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments

3. Secondary Outcome

Title	Change in Transition Dyspnea Index (TDI) Focal Score
Description	The TDI measures the change from baseline in severity of breathlessness in symptomatic patients. The TDI contains a rating for 3 categories (functional impairment, magnitude of task, magnitude of effort).TDI scale ranges from -3 (major deterioration) to +3 (major improvement) including a 0 score to indicate "no change". The 3 categories are added to obtain a focal score ranging from -9 (including 0) to +9.
Time Frame	Week 24 of treatment

Outcome Measure Data

Analysis Population Description

ITT Population defined as all randomized patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment

Arm/Group Title	Aclidinium/Formoterol 400/12 μg	Aclidinium/Formoterol 400/6 μg	Aclidinium 400 μg	Formoterol 12 μg	Placebo
Arm/Group Description	Fixed-dose combination (FDC) administered BID by inhalation	Fixed-dose combination (FDC) administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation
Measure Participants	335	333	337	332	331
Least Squares Mean (Standard Error) [Scores on a scale]	2.017 (0.203)	1.977 (0.199)	1.558 (0.201)	1.522 (0.201)	0.582 (0.216)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aclidinium/Formoterol 400/12 μg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Treatment group, sex, smoking-status, visit, and treatment group-by-visit as factors; visit, age baseline BDI/SGRQ as covariates
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	1.436
	Confidence Interval	(2-Sided) 95%; 0.854 to 2.018
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.297
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aclidinium/Formoterol 400/6 μg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Treatment group, sex, smoking-status, visit, and treatment group-by-visit as factors; visit, age baseline BDI/SGRQ as covariates
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	1.395
	Confidence Interval	(2-Sided) 95%; 0.818 to 1.972
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.294
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score
Description	St George's Respiratory Questionnaire (SGRQ) measures COPD-specific health outcomes and consists of 2 parts with 3 dimension scores (a symptom score and an activity and impacts score). SGRQ total score is the sum of these scores and ranges from 0 (best health status) to 100 (worst health status).
Time Frame	Week 24 of treatment

Outcome Measure Data

Analysis Population Description

ITT Population defined as all randomized patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment

Arm/Group Title	Aclidinium/Formoterol 400/12 μg	Aclidinium/Formoterol 400/6 μg	Aclidinium 400 μg	Formoterol 12 μg	Placebo
Arm/Group Description	Fixed-dose combination (FDC) administered BID by inhalation	Fixed-dose combination (FDC) administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation	Administered BID by inhalation
Measure Participants	335	333	337	332	331
Least Squares Mean (Standard Error) [Scores on a scale]	-6.568 (0.740)	-5.942 (0.728)	-6.438 (0.738)	-4.701 (0.742)	-2.215 (0.779)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aclidinium/Formoterol 400/12 μg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Treatment group, sex, smoking-status, visit, and treatment group-by-visit as factors; visit, age baseline BDI/SGRQ as covariates
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-4.353
	Confidence Interval	(2-Sided) 95%; -6.462 to -2.244
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.075
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aclidinium/Formoterol 400/6 μg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Mixed Models Analysis
	Comments	Treatment group, sex, smoking-status, visit, and treatment group-by-visit as factors; visit, age baseline BDI/SGRQ as covariates
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-3.728
	Confidence Interval	(2-Sided) 95%; -5.819 to -1.637
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.066
	Estimation Comments

Adverse Events

Time Frame	Week 26 ± 5 days
Adverse Event Reporting Description	Safety population comprised all patients randomized to a treatment group who received at least 1 dose of double-blind investigational treatment.
Arm/Group Title	Aclidinium/Formoterol 400/12 μg		Aclidinium/Formoterol 400/6 μg		Aclidinium 400 μg		Formoterol 12 μg		Placebo
Arm/Group Description	Fixed-dose combination (FDC) administered BID by inhalation		Fixed-dose combination (FDC) administered BID by inhalation		Administered BID by inhalation		Administered BID by inhalation		Administered BID by inhalation
All Cause Mortality
	Aclidinium/Formoterol 400/12 μg		Aclidinium/Formoterol 400/6 μg		Aclidinium 400 μg		Formoterol 12 μg		Placebo
	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)
Serious Adverse Events
	Aclidinium/Formoterol 400/12 μg		Aclidinium/Formoterol 400/6 μg		Aclidinium 400 μg		Formoterol 12 μg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/335 (5.7%)		18/333 (5.4%)		17/337 (5%)		15/332 (4.5%)		12/332 (3.6%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Anaemia	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		1/332 (0.3%)
Coagulopathy	0/335 (0%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		1/332 (0.3%)
Haemorrhagic diathesis	0/335 (0%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		1/332 (0.3%)
Cardiac disorders
Acute myocardial infarction	1/335 (0.3%)		1/333 (0.3%)		0/337 (0%)		1/332 (0.3%)		1/332 (0.3%)
Acute coronary syndrome	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Angina pectoris	0/335 (0%)		2/333 (0.6%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Angina unstable	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		1/332 (0.3%)
Atrial fibrillation	0/335 (0%)		1/333 (0.3%)		1/337 (0.3%)		1/332 (0.3%)		2/332 (0.6%)
Coronary artery disease	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		1/332 (0.3%)
Myocardial infarction	0/335 (0%)		2/333 (0.6%)		1/337 (0.3%)		1/332 (0.3%)		0/332 (0%)
Right ventricular failure	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Ear and labyrinth disorders
Vertigo	1/335 (0.3%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Gastrointestinal disorders
Colitis	1/335 (0.3%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Diverticulum	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Abdominal pain	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Abdominal pain upper	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Abdominal wall haematoma	0/335 (0%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		1/332 (0.3%)
Constipation	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Gastrointestinal necrosis	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Gastrooesophageal reflux disease	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Hiatus hernia	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Nausea	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Vomiting	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
General disorders
Asthenia	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Non-cardiac chest pain	1/335 (0.3%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Fatigue	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Death	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Hepatobiliary disorders
Cholecystitis acute	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Hepatitis	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Infections and infestations
Pneumonia	2/335 (0.6%)		1/333 (0.3%)		1/337 (0.3%)		3/332 (0.9%)		3/332 (0.9%)
Appendicitis perforated	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Diverticulitis	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		1/332 (0.3%)
Gastroenteritis	0/335 (0%)		1/333 (0.3%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Herpes zoster	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Kidney infection	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Lobar pneumonia	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Parainfluenzae virus infection	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Pyelonephritis	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Sepsis	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Urinary tract infection bacterial	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Injury, poisoning and procedural complications
Alcohol poisoning	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Fall	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Femur fracture	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Hip fracture	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Overdose	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		1/332 (0.3%)
Investigations
International normalised ratio increased	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Transaminases increased	0/335 (0%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		1/332 (0.3%)
Metabolism and nutrition disorders
Dehydration	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Gout	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Hyponatraemia	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Hypovolaemia	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Intervertebral disc degeneration	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Cervix carcinoma	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Prostate cancer	1/335 (0.3%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Bladder cancer	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Non-Hodgkin's lymphoma	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Oesophageal adenocarcinoma	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Squamous cell carcinoma of the hypopharynx	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Nervous system disorders
Convulsion	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Cerebrovascular accident	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		2/332 (0.6%)
Dysarthria	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Headache	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Transient ischaemic attack	0/335 (0%)		2/333 (0.6%)		0/337 (0%)		0/332 (0%)		1/332 (0.3%)
VIIth nerve paralysis	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Psychiatric disorders
Suicidal ideation	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Depression	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Suicide attempt	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Renal and urinary disorders
Renal failure acute	1/335 (0.3%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Nephrolithiasis	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Nephropathy	0/335 (0%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		1/332 (0.3%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Acute respiratory failure	0/335 (0%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		1/332 (0.3%)
Bronchiectasis	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Pulmonary mass	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Pulmonary oedema	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Respiratory acidosis	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Respiratory failure	0/335 (0%)		0/333 (0%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Vascular disorders
Peripheral vascular disorder	1/335 (0.3%)		0/333 (0%)		0/337 (0%)		0/332 (0%)		0/332 (0%)
Aortic aneurysm	0/335 (0%)		0/333 (0%)		1/337 (0.3%)		0/332 (0%)		0/332 (0%)
Hypertension	0/335 (0%)		1/333 (0.3%)		0/337 (0%)		1/332 (0.3%)		0/332 (0%)
Other (Not Including Serious) Adverse Events
	Aclidinium/Formoterol 400/12 μg		Aclidinium/Formoterol 400/6 μg		Aclidinium 400 μg		Formoterol 12 μg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/335 (18.8%)		65/333 (19.5%)		57/337 (16.9%)		74/332 (22.3%)		58/332 (17.5%)
Infections and infestations
Nasopharyngitis	16/335 (4.8%)		17/333 (5.1%)		12/337 (3.6%)		22/332 (6.6%)		12/332 (3.6%)
Respiratory, thoracic and mediastinal disorders
Cough	17/335 (5.1%)		13/333 (3.9%)		7/337 (2.1%)		10/332 (3%)		12/332 (3.6%)
Chronic obstructive pulmonary disease	51/335 (15.2%)		49/333 (14.7%)		57/337 (16.9%)		53/332 (16%)		58/332 (17.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Publication of the results by the Investigator will be subject to mutual agreement between the investigator and sponsor.