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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01437540
• Collaborator: (none)
• Enrollment: 590
• Locations: 137
• Arms: 2
• Actual Duration (Months): 19.4
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the long-term safety and tolerability of inhaled aclidinium bromide/formoterol in patients with moderate to severe, stable chronic obstructive pulmonary disease (COPD).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 590 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Long-Term, Randomized, Study of the Safety and Tolerability of a Fixed-Dose Combination of Aclidinium Bromide/Formoterol Fumarate Compared With Formoterol Fumarate in Patients With Moderate to Severe, Stable Chronic Obstructive Pulmonary Disease (COPD)
• Actual Study Start Date: Sep 19, 2011
• Actual Primary Completion Date: Mar 31, 2013
• Actual Study Completion Date: Apr 30, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Inhaled aclidinium bromide 400 μg/formoterol fumarate 12 μg fixed dose combination (FDC), high dose twice per day	Drug: Aclidinium Bromide/Formoterol Fumarate; Inhaled aclidinium bromide 400 μg/formoterol fumarate 12 μg, high dose twice per day
Active Comparator: 2 Inhaled formoterol fumarate 12 μg, twice per day	Drug: Formoterol Fumarate; Inhaled formoterol fumarate 12 μg, twice per day

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients to Experience at Least One Treatment-emergent Adverse Event (TEAE) [Up to study Week 56 ± 3 days]

   TEAEs were coded Version 16.0 of the Medical Dictionary for Regulatory Activities (MedDRA)

Secondary Outcome Measures

1. Percentage of Patients to Experience Any Potentially Clinically Significant (PCS) Post-baseline Change in Clinical Laboratory Values for Hematology, Chemistry or Urinalysis at the End of the Study [Up to study Week 52]

   <0.85 x lower limit of normal (LLN) or > 1.15 upper limit of normal (ULN) for hemoglobin, hematocrit, red blood cell, platelet, white blood cell, neutrophil and lymphocyte counts >1.15 × ULN for eosinophil, basophil and monocyte counts >1.15 x ULN for aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase, total bilirubin, creatinine kinase, lactate dehydrogenase, blood urea nitrogen, creatinine, uric acid, total cholesterol, triglycerides <0.85 x LLN or >1.15 ULN for fasting glucose, calcium, phosphorus, total protein and albumin <0.95 x LLN or >1.05 x ULN for sodium, potassium and chloride Urinary blood, ketones or pH <0.85 x LLN or > 1.15 ULN

2. Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure [Up to study Week 56 ± 3 days]

   Systolic BP ≥180 mmHg and increase ≥20 mmHg from baseline or ≤90 mmHg and decrease ≥20 mmHg from baseline; Diastolic BP ≥105 mmHg and increase ≥15 mmHg from baseline or ≤50 mmHg and decrease ≥15 mmHg from baseline; Pulse rate ≥ 110 bpm and increase ≥ 15% from baseline or ≤ 50 bpm and decrease ≥15% from baseline

3. Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline [Up to study Week 56 ± 3 days]

   Potentially clinically significant changes were defined as listed in the table below for QT interval, QTcB, QTcF, QRS interval, PR interval and heart rate (HR)

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Current or former cigarette smokers 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 Global Initiative for Chronic Obstructive Lung Disease guidelines and stable airway obstruction.

Exclusion Criteria:

• Patients who have been hospitalized for an acute COPD exacerbation within three months prior to Visit 1

• Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the six weeks before Visit 1.

• Patients with any clinically significant respiratory conditions other than COPD

• Clinical history that suggests that the patient has asthma as opposed to COPD

• Chronic use of oxygen therapy ≥ 15 hours/day

• Patients with clinically significant cardiovascular conditions

• Patients with uncontrolled infection that may place the patient at risk resulting from human immunodeficiency virus (HIV), active hepatitis and/or patients with diagnosed active tuberculosis

• Patients with a history of hypersensitivity reaction to inhaled anticholinergics,

• Patients with Stage II hypertension, defined as systolic pressure of 160 and above, and/or diastolic pressure of 100 and above

• Current diagnosis of cancer other than basal or squamous cell skin cancer

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Forest Investigative Site 1162	Birmingham	Alabama	United States	35209
2	Forest Investigative Site 1493	Birmingham	Alabama	United States	35209
3	Forest Investigative Site 1620	Birmingham	Alabama	United States	35235
4	Forest Investigative Site 1127	Mobile	Alabama	United States	36608
5	Forest Investigative Site 1613	Chandler	Arizona	United States	85224
6	Forest Investigative Site 1623	Peoria	Arizona	United States	85381
7	Forest Investigative Site 1582	Phoenix	Arizona	United States	85012
8	Forest Investigative Site 1379	Phoenix	Arizona	United States	85018
9	Forest Investigative Site 1581	Phoenix	Arizona	United States	85020
10	Forest Investigative Site 1571	Phoenix	Arizona	United States	85050
11	Forest Investigative Site 1596	Fort Smith	Arkansas	United States	72901
12	Forest Investigative Site 1547	Encinitas	California	United States	92024
13	Forest Investigative Site 1088	Lakewood	California	United States	90712
14	Forest Investigative Site 1624	Los Angeles	California	United States	90025
15	Forest Investigative Site 1927	Los Angeles	California	United States	90048
16	Forest Investigative Site 1388	Paramount	California	United States	90723
17	Forest Investigative Site 1503	San Diego	California	United States	92128
18	Forest Investigative Site 1374	Torrance	California	United States	90505
19	Forest Investigative Site 1331	Vista	California	United States	92083
20	Forest Investigative Site 2039	Walnut Creek	California	United States	94598
21	Forest Investigative Site 1597	Boulder	Colorado	United States	80304
22	Forest Investigative Site 1137	Colorado Springs	Colorado	United States	80907
23	Forest Investigative Site 0892	Denver	Colorado	United States	80206
24	Forest Investigative Site 2037	Fort Collins	Colorado	United States	80528
25	Forest Investigative Site 1327	Wheat Ridge	Colorado	United States	80033
26	Forest Investigative Site 2045	Wheat Ridge	Colorado	United States	80033
27	Forest Investigative Site 1589	Norwalk	Connecticut	United States	06851
28	Forest Investigative Site 1598	Stamford	Connecticut	United States	06902
29	Forest Investigative Site 1154	Brandon	Florida	United States	33511
30	Forest Investigative Site 1944	Brandon	Florida	United States	33511
31	Forest Investigative Site 1152	Clearwater	Florida	United States	33765
32	Forest Investigative Site 1617	Debary	Florida	United States	32713
33	Forest Investigative Site 1959	Debary	Florida	United States	32713
34	Forest Investigative Site 1516	Edgewater	Florida	United States	32132
35	Forest Investigative Site 1403	Hollywood	Florida	United States	33024
36	Forest Investigative Site 1556	Orlando	Florida	United States	32822
37	Forest Investigative Site 1542	Ormond Beach	Florida	United States	32174
38	Forest Investigative Site 0974	Pensacola	Florida	United States	32504
39	Forest Investigative Site 2047	Tampa	Florida	United States	33613
40	Forest Investigative Site 1565	Venice	Florida	United States	34292
41	Forest Investigative Site 1851	Atlanta	Georgia	United States	30329
42	Forest Investigative Site 0980	Atlanta	Georgia	United States	30342
43	Forest Investigative Site 1567	Atlanta	Georgia	United States	30342
44	Forest Investigative Site 1607	Lawrenceville	Georgia	United States	30046
45	Forest Investigative Site 1409	O'Fallon	Illinois	United States	62269
46	Forest Investigative Site 2051	River Forest	Illinois	United States	60305
47	Forest Investigative Site 1604	Springfield	Illinois	United States	62702
48	Forest Investigative Site 1576	Evansville	Indiana	United States	47713
49	Forest Investigative Site 1549	Council Bluffs	Iowa	United States	51503
50	Forest Investigative Site 2033	Bowling Green	Kentucky	United States	42101
51	Forest Investigative Site 2085	Crescent Springs	Kentucky	United States	41017
52	Forest Investigative Site 1336	Louisville	Kentucky	United States	40215
53	Forest Investigative Site 2024	Lafayette	Louisiana	United States	70503
54	Forest Investigative Site 1430	New Orleans	Louisiana	United States	70115
55	Forest Investigative Site 1360	Sunset	Louisiana	United States	70584
56	Forest Investigative Site 1566	Auburn	Maine	United States	04210
57	Forest Investigative Site 1333	Baltimore	Maryland	United States	21236
58	Forest Investigative Site 1622	Columbia	Maryland	United States	21044
59	Forest Investigative Site 1590	Towson	Maryland	United States	21204
60	Forest Investigative Site 1570	Fall River	Massachusetts	United States	02720
61	Forest Investigative Site 1546	Haverhill	Massachusetts	United States	01830
62	Forest Investigative Site 1029	North Dartmouth	Massachusetts	United States	02747
63	Forest Investigative Site 1595	Worcestor	Massachusetts	United States	01605
64	Forest Investigative Site 1605	Traverse City	Michigan	United States	49684
65	Forest Investigative Site 1527	Fridley	Minnesota	United States	55432
66	Forest Investigative Site 1124	Minneapolis	Minnesota	United States	55407
67	Forest Investigative Site 1619	Plymouth	Minnesota	United States	55441
68	Forest Investigative Site 1587	Chesterfield	Missouri	United States	63017
69	Forest Investigative Site 1572	Jefferson City	Missouri	United States	65109
70	Forest Investigative Site 1399	St. Louis	Missouri	United States	63141
71	Forest Investigative Site 1599	St. Louis	Missouri	United States	63141
72	Forest Investigative Site 1831	Bozeman	Montana	United States	59718
73	Forest Investigative Site 1400	Missoula	Montana	United States	59808
74	Forest Investigative Site 1609	Bellevue	Nebraska	United States	68123
75	Forest Investigative Site 1616	Lincoln	Nebraska	United States	68506
76	Forest Investigative Site 1615	Omaha	Nebraska	United States	68134
77	Forest Investigative Site 1562	Las Vegas	Nevada	United States	89183
78	Forest Investigative Site 1610	Rochester	New Hampshire	United States	03867
79	Forest Investigative Site 1558	Brick	New Jersey	United States	08723
80	Forest Investigative Site 1559	Cherry Hill	New Jersey	United States	08003
81	Forest Investigative Site 1394	Ocean	New Jersey	United States	07712
82	Forest Investigative Site 2084	Summit	New Jersey	United States	07901
83	Forest Investigative Site 0972	Brooklyn	New York	United States	11229
84	Forest Investigative Site 1163	New York	New York	United States	10016
85	Forest Investigative Site 1425	New York	New York	United States	10028
86	Forest Investigative Site 1554	Newburgh	New York	United States	12550
87	Forest Investigative Site 1563	Syracuse	New York	United States	13210
88	Forest Investigative Site 1557	Raleigh	North Carolina	United States	27612
89	Forest Investigative Site 1588	Shelby	North Carolina	United States	28152
90	Forest Investigative Site 1553	Wilmington	North Carolina	United States	28401
91	Forest Investigative Site 1550	Winston-Salem	North Carolina	United States	27103
92	Forest Investigative Site 1134	Canton	Ohio	United States	44718
93	Forest Investigative Site 1594	Cincinnati	Ohio	United States	45224
94	Forest Investigative Site 2028	Cincinnati	Ohio	United States	45242
95	Forest Investigative Site 1541	Marion	Ohio	United States	43302
96	Forest Investigative Site 1530	Toledo	Ohio	United States	43608
97	Forest Investigative Site 1393	Zanesville	Ohio	United States	43701
98	Forest Investigative Site 1612	Ashland	Oregon	United States	97520
99	Forest Investigative Site 1575	Corvallis	Oregon	United States	97330
100	Forest Investigative Site 1081	Eugene	Oregon	United States	97404
101	Forest Investigative Site 1580	Portland	Oregon	United States	97213
102	Forest Investigative Site 1552	Portland	Oregon	United States	97220
103	Forest Investigative Site 1574	Beaver	Pennsylvania	United States	15009
104	Forest Investigative Site 1577	Beaver	Pennsylvania	United States	15009
105	Forest Investigative Site 1126	Bethlehem	Pennsylvania	United States	18020
106	Forest Investigative Site 1423	Erie	Pennsylvania	United States	16506
107	Forest Investigative Site 1504	Hershey	Pennsylvania	United States	17033
108	Forest Investigative Site 1569	Pittsburgh	Pennsylvania	United States	15213
109	Forest Investigative Site 1548	Pittsburgh	Pennsylvania	United States	15236
110	Forest Investigative Site 1146	Pittsburgh	Pennsylvania	United States	15243
111	Forest Investigative Site 1560	Pittsburgh	Pennsylvania	United States	15243
112	Forest Investigative Site 1449	Tipton	Pennsylvania	United States	16684
113	Forest Investigative Site 1564	Uniontown	Pennsylvania	United States	15401
114	Forest Investigative Site 1144	Johnston	Rhode Island	United States	02919
115	Forest Investigative Site 2072	Charleston	South Carolina	United States	29406
116	Forest Investigative Site 1568	Easley	South Carolina	United States	29640
117	Forest Investigative Site 1506	Greenville	South Carolina	United States	29615
118	Forest Investigative Site 1601	Greer	South Carolina	United States	29651
119	Forest Investigative Site 0900	Spartanburg	South Carolina	United States	29303
120	Forest Investigative Site 1450	Union	South Carolina	United States	29379
121	Forest Investigative Site 1365	Rapid City	South Dakota	United States	57702
122	Forest Investigative Site 1440	Arlington	Texas	United States	76012
123	Forest Investigative Site 1954	Austin	Texas	United States	78731
124	Forest Investigative Site 1155	Dallas	Texas	United States	75231
125	Forest Investigative Site 1328	Dallas	Texas	United States	75231
126	Forest Investigative Site 1332	El Paso	Texas	United States	79903
127	Forest Investigative Site 2012	Fort Worth	Texas	United States	76104
128	Forest Investigative Site 1902	Killeen	Texas	United States	76543
129	Forest Investigative Site 1498	San Antonio	Texas	United States	78215
130	Forest Investigative Site 1614	San Antonio	Texas	United States	78228
131	Forest Investigative Site 1906	San Antonio	Texas	United States	78229
132	Forest Investigative Site 2004	San Antonio	Texas	United States	78229
133	Forest Investigative Site 1600	Magna	Utah	United States	84044
134	Forest Investigative Site 1480	Abingdon	Virginia	United States	24210
135	Forest Investigative Site 1579	Alexandria	Virginia	United States	22304
136	Forest Investigative Site 1142	Spokane	Washington	United States	99204
137	Forest Investigative Site 1573	Spokane	Washington	United States	99216

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Esther Garcia, MD, AstraZeneca

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• lac-md-32-synopsis

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01437540
• Other Study ID Numbers: LAC-MD-32
• First Posted: Sep 21, 2011
• Last Update Posted: May 11, 2017
• Last Verified: Mar 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	The study was conducted at 127 centers in the United States The first patient was screened in September 2011 and the last patient visit was in March 2013
Pre-assignment Detail	The study consisted of a 2- to 3-week run-in period designed to assess the stability of patients' disease and establish each patient's baseline characteristics 1063 patients were screened for eligibility; 473 were considered screen failures (main reason [406/473] inclusion/exclusion criteria not met)

Arm/Group Title	Aclidinium/Formoterol 400 μg/12 μg	Formoterol 12 μg
Arm/Group Description	Aclidinium bromide/formoterol 400 μg/12 μg administered BID via dry-powder inhaler	Formoterol 12 μg administered BID via dry-powder inhaler
Period Title: Overall Study
STARTED	392	198
COMPLETED	265	133
NOT COMPLETED	127	65

Baseline Characteristics

Arm/Group Title	Aclidinium/Formoterol 400 μg/12 μg	Formoterol 12 μg	Total
Arm/Group Description	Aclidinium bromide/formoterol 400 μg/12 μg administered BID via dry-powder inhaler	Formoterol 12 μg administered BID via dry-powder inhaler	Total of all reporting groups
Overall Participants	392	198	590
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.9 (9.3)	64.7 (9.4)	64.2 (9.4)
Sex: Female, Male (Count of Participants)
Female	176 44.9%	89 44.9%	265 44.9%
Male	216 55.1%	109 55.1%	325 55.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients to Experience at Least One Treatment-emergent Adverse Event (TEAE)
Description	TEAEs were coded Version 16.0 of the Medical Dictionary for Regulatory Activities (MedDRA)
Time Frame	Up to study Week 56 ± 3 days

Outcome Measure Data

Analysis Population Description

Safety Population defined as all randomized patients who took at least one dose of double-blind investigational product

Arm/Group Title	Aclidinium/Formoterol 400 μg/12 μg	Formoterol 12 μg
Arm/Group Description	Aclidinium bromide/formoterol 400 μg/12 μg administered BID via dry-powder inhaler	Formoterol 12 μg administered BID via dry-powder inhaler
Measure Participants	392	198
Number [Percentage of participants]	71.4 18.2%	65.7 33.2%

2. Secondary Outcome

Title	Percentage of Patients to Experience Any Potentially Clinically Significant (PCS) Post-baseline Change in Clinical Laboratory Values for Hematology, Chemistry or Urinalysis at the End of the Study
Description	<0.85 x lower limit of normal (LLN) or > 1.15 upper limit of normal (ULN) for hemoglobin, hematocrit, red blood cell, platelet, white blood cell, neutrophil and lymphocyte counts >1.15 × ULN for eosinophil, basophil and monocyte counts >1.15 x ULN for aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase, total bilirubin, creatinine kinase, lactate dehydrogenase, blood urea nitrogen, creatinine, uric acid, total cholesterol, triglycerides <0.85 x LLN or >1.15 ULN for fasting glucose, calcium, phosphorus, total protein and albumin <0.95 x LLN or >1.05 x ULN for sodium, potassium and chloride Urinary blood, ketones or pH <0.85 x LLN or > 1.15 ULN
Time Frame	Up to study Week 52

Outcome Measure Data

Analysis Population Description

Patients with available non-potentially clinically significant baseline value and at least one post-baseline assessment

Arm/Group Title	Aclidinium/Formoterol 400 μg/12 μg	Formoterol 12 μg
Arm/Group Description	Aclidinium bromide/formoterol 400 μg/12 μg administered BID via dry-powder inhaler	Formoterol 12 μg administered BID via dry-powder inhaler
Measure Participants	380	195
Number [Percentage of participants]	63.9 16.3%	62.1 31.4%

3. Secondary Outcome

Title	Percentage of Patients to Experience a Potentially Clinically Significant (PCS) Change in Pulse Rate, Systolic and Diastolic Blood Pressure
Description	Systolic BP ≥180 mmHg and increase ≥20 mmHg from baseline or ≤90 mmHg and decrease ≥20 mmHg from baseline; Diastolic BP ≥105 mmHg and increase ≥15 mmHg from baseline or ≤50 mmHg and decrease ≥15 mmHg from baseline; Pulse rate ≥ 110 bpm and increase ≥ 15% from baseline or ≤ 50 bpm and decrease ≥15% from baseline
Time Frame	Up to study Week 56 ± 3 days

Outcome Measure Data

Analysis Population Description

Patients with baseline and at least 1 post-baseline assessment of vital signs for each parameter

Arm/Group Title	Aclidinium/Formoterol 400 μg/12 μg	Formoterol 12 μg
Arm/Group Description	Aclidinium bromide/formoterol 400 μg/12 μg administered BID via dry-powder inhaler	Formoterol 12 μg administered BID via dry-powder inhaler
Measure Participants	389	198
Systolic BP ≥180 mmHg and increase ≥20 mmHg	0.3	0.5
Systolic BP ≤90 mmHg and decrease ≥20 mmHg	1.5	1.0
Diastolic BP ≥105 mmHg and increase ≥15 mmHg	0	0.5
Diastolic BP ≤50 mmHg and decrease ≥15 mmHg	0.3	1.0
Pulse rate ≥ 110 bpm and increase ≥ 15%	0.8	0.5
Pulse rate ≤ 50 bpm and decrease ≥15%	0	0

4. Secondary Outcome

Title	Percentage of Patients to Experience Potentially Clinically Significant Changes in ECG From Baseline
Description	Potentially clinically significant changes were defined as listed in the table below for QT interval, QTcB, QTcF, QRS interval, PR interval and heart rate (HR)
Time Frame	Up to study Week 56 ± 3 days

Outcome Measure Data

Analysis Population Description

Patients with baseline and at least 1 post-baseline assessment value for each parameter

Arm/Group Title	Aclidinium/Formoterol 400 μg/12 μg	Formoterol 12 μg
Arm/Group Description	Aclidinium bromide/formoterol 400 μg/12 μg administered BID via dry-powder inhaler	Formoterol 12 μg administered BID via dry-powder inhaler
Measure Participants	392	198
QT interval change from baseline >30 msec	42.0	44.7
QT interval >480 msec	3.9	2.0
QTcB change from baseline >30 msec	31.1	30.3
QTcB value >480 msec	3.1	4.5
QTcF change from baseline >30 msec	21.5	22.7
QTcF value >480 msec	1.5	1.5
QRS interval ≥100 msec and increase ≥25% from base	2.0	1.0
PR interval ≥200 msec and increase ≥25% from base	2.8	1.0
HR ≥110 bpm and decrease ≥15% from baseline	2.6	1.0
HR ≤50 bpm and decrease ≥15% from baseline	4.6	4.0

Adverse Events

Time Frame	Up to study Week 56 ± 3 days
Arm/Group Title	Aclidinium/Formoterol 400 μg/12 μg		Formoterol 12 μg
Arm/Group Description	Aclidinium bromide/formoterol 400 μg/12 μg administered BID via dry-powder inhaler		Formoterol 12 μg administered BID via dry-powder inhaler
All Cause Mortality
	Aclidinium/Formoterol 400 μg/12 μg		Formoterol 12 μg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Aclidinium/Formoterol 400 μg/12 μg		Formoterol 12 μg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/392 (9.7%)		21/198 (10.6%)
Blood and lymphatic system disorders
Hilar lymphadenopathy	1/392 (0.3%)		0/198 (0%)
Cardiac disorders
Atrial fibrillation	2/392 (0.5%)		1/198 (0.5%)
Angina pectoris	1/392 (0.3%)		0/198 (0%)
Atrial flutter	1/392 (0.3%)		0/198 (0%)
Cardiac failure congestive	1/392 (0.3%)		1/198 (0.5%)
Cardio-respiratory arrest	1/392 (0.3%)		0/198 (0%)
Coronary artery occlusion	1/392 (0.3%)		0/198 (0%)
Ventricular tachycardia	1/392 (0.3%)		0/198 (0%)
Coronary artery disease	0/392 (0%)		1/198 (0.5%)
Mitral valve stenosis	0/392 (0%)		1/198 (0.5%)
Eye disorders
Vision blurred	0/392 (0%)		1/198 (0.5%)
Gastrointestinal disorders
Abdominal pain	2/392 (0.5%)		1/198 (0.5%)
Gastric ulcer	1/392 (0.3%)		0/198 (0%)
Melaena	1/392 (0.3%)		0/198 (0%)
Mesenteric artery stenosis	1/392 (0.3%)		0/198 (0%)
Pancreatitis	1/392 (0.3%)		0/198 (0%)
Colonic stenosis	0/392 (0%)		1/198 (0.5%)
Femoral hernia, obstructive	0/392 (0%)		1/198 (0.5%)
Gastric haemorrhage	0/392 (0%)		1/198 (0.5%)
Gastrointestinal haemorrhage	0/392 (0%)		1/198 (0.5%)
Inguinal hernia, obstructive	0/392 (0%)		1/198 (0.5%)
Pancreatitis acute	0/392 (0%)		1/198 (0.5%)
Small intestinal obstruction	0/392 (0%)		1/198 (0.5%)
General disorders
Death	2/392 (0.5%)		0/198 (0%)
Non-cardiac chest pain	2/392 (0.5%)		0/198 (0%)
Immune system disorders
Sarcoidosis	1/392 (0.3%)		0/198 (0%)
Infections and infestations
Pneumonia	4/392 (1%)		1/198 (0.5%)
Abscess intestinal	1/392 (0.3%)		0/198 (0%)
Cellulitis	1/392 (0.3%)		0/198 (0%)
Diverticulitis	1/392 (0.3%)		1/198 (0.5%)
Lobar pneumonia	1/392 (0.3%)		0/198 (0%)
Urinary tract infection	1/392 (0.3%)		1/198 (0.5%)
Gastroenteritis	0/392 (0%)		1/198 (0.5%)
Liver abscess	0/392 (0%)		1/198 (0.5%)
Injury, poisoning and procedural complications
Fall	1/392 (0.3%)		0/198 (0%)
Lumbar vertebral fracture	1/392 (0.3%)		0/198 (0%)
Radius fracture	1/392 (0.3%)		0/198 (0%)
Tibia fracture	1/392 (0.3%)		0/198 (0%)
Urinary retention postoperative	1/392 (0.3%)		0/198 (0%)
Chemical burn of skin	0/392 (0%)		1/198 (0.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/392 (0.3%)		0/198 (0%)
Flank pain	1/392 (0.3%)		0/198 (0%)
Joint effusion	1/392 (0.3%)		0/198 (0%)
Lumbar spinal stenosis	1/392 (0.3%)		0/198 (0%)
Neck pain	1/392 (0.3%)		0/198 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/392 (0.3%)		0/198 (0%)
Colon cancer	1/392 (0.3%)		0/198 (0%)
Endometrial adenocarcinoma	1/392 (0.3%)		0/198 (0%)
Lung adenocarcinoma stage IV	1/392 (0.3%)		0/198 (0%)
Lung cancer metastatic	1/392 (0.3%)		0/198 (0%)
Lung carcinoma cell type unspecified stage III	1/392 (0.3%)		0/198 (0%)
Lung neoplasm malignant	1/392 (0.3%)		0/198 (0%)
Metastases to lymph nodes	1/392 (0.3%)		0/198 (0%)
Non-Hodgkin's lymphoma	1/392 (0.3%)		0/198 (0%)
Intestinal adenocarcinoma	0/392 (0%)		1/198 (0.5%)
Squamous cell carcinoma of lung	0/392 (0%)		1/198 (0.5%)
Nervous system disorders
Carotid artery disease	1/392 (0.3%)		0/198 (0%)
Headache	1/392 (0.3%)		0/198 (0%)
Syncope	1/392 (0.3%)		0/198 (0%)
Transient ischaemic attack	1/392 (0.3%)		0/198 (0%)
VIIth nerve paralysis	1/392 (0.3%)		0/198 (0%)
Brain mass	0/392 (0%)		1/198 (0.5%)
Cerebral haemorrhage	0/392 (0%)		1/198 (0.5%)
Convulsion	0/392 (0%)		1/198 (0.5%)
Dizziness	0/392 (0%)		1/198 (0.5%)
Psychiatric disorders
Completed suicide	1/392 (0.3%)		0/198 (0%)
Renal and urinary disorders
Renal failure	1/392 (0.3%)		0/198 (0%)
Calculus ureteric	0/392 (0%)		1/198 (0.5%)
Renal failure acute	0/392 (0%)		1/198 (0.5%)
Reproductive system and breast disorders
Cystocele	1/392 (0.3%)		0/198 (0%)
Rectocele	1/392 (0.3%)		0/198 (0%)
Uterine prolapse	1/392 (0.3%)		0/198 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic respiratory failure	1/392 (0.3%)		0/198 (0%)
Epistaxis	1/392 (0.3%)		0/198 (0%)
Pneumonitis	1/392 (0.3%)		0/198 (0%)
Pulmonary embolism	1/392 (0.3%)		0/198 (0%)
Respiratory failure	1/392 (0.3%)		1/198 (0.5%)
Dyspnoea	0/392 (0%)		1/198 (0.5%)
Vascular disorders
Hypertension	1/392 (0.3%)		0/198 (0%)
Peripheral vascular disorder	1/392 (0.3%)		0/198 (0%)
Aortic stenosis	0/392 (0%)		1/198 (0.5%)
Other (Not Including Serious) Adverse Events
	Aclidinium/Formoterol 400 μg/12 μg		Formoterol 12 μg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	164/392 (41.8%)		88/198 (44.4%)
Gastrointestinal disorders
Nausea	7/392 (1.8%)		11/198 (5.6%)
Infections and infestations
Nasopharyngitis	25/392 (6.4%)		9/198 (4.5%)
Sinusitis	20/392 (5.1%)		11/198 (5.6%)
Upper respiratory tract infection	18/392 (4.6%)		12/198 (6.1%)
Urinary tract infection	26/392 (6.6%)		11/198 (5.6%)
Psychiatric disorders
Anxiety	23/392 (5.9%)		5/198 (2.5%)
Respiratory, thoracic and mediastinal disorders
Cough	10/392 (2.6%)		10/198 (5.1%)
Chronic obstructive pulmonary disease	106/392 (27%)		57/198 (28.8%)

Limitations/Caveats

The objective of the study is to assess the long-term safety and tolerability of inhaled aclidinium bromide/formoterol fixed-dose combination (FDC) Therefore there were were no primary and secondary efficacy assessments

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Certain Agreements

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

Publication of the results by the principal investigator (PI) will be subject to mutual agreement between the PI and sponsor