ASCENT COPD: Evaluate the Effect of Aclidinium Bromide on Long-term Cardiovascular Safety and Exacerbations in Moderate to Very Severe COPD Patients.

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01966107
• Collaborator: (none)
• Enrollment: 3,635
• Locations: 468
• Arms: 2
• Actual Duration (Months): 47.2
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The Objectives of this study are to assess the safety of Aclidinium bromide on major adverse cardiovascular events (MACE), to assess the overall safety of Aclidinium bromide and to assess whether Aclidinium bromide reduces moderate or severe COPD exacerbations. This study is a double-blind, randomized, placebo controlled, parallel-group study to evaluate the effect of Aclidinium bromide on the cardiovascular safety and COPD exacerbations in patients with moderate to very severe COPD, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.

Condition or Disease	Intervention/Treatment	Phase
COPD; Chronic Obstructive Pulmonary Disease; Moderate to Very Severe COPD	Drug: Aclidinium Bromide; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 3635 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Double-blind, Randomized, Placebo-controlled, Parallel-group, Phase IV Study to Evaluate the Effect of Aclidinium Bromide on Long-term Cardiovascular Safety and COPD Exacerbations in Patients With Moderate to Very Severe COPD (ASCENT COPD)
• Actual Study Start Date: Oct 16, 2013
• Actual Primary Completion Date: Sep 21, 2017
• Actual Study Completion Date: Sep 21, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Aclidinium Bromide Two-week washout/run-in period [for patients on a long-acting muscarinic antagonist (LAMA)] followed by a maximum of 36-month double-blind treatment period.	Drug: Aclidinium Bromide; 400 μg, twice per day, oral administration via a multi-dose dry-powder inhaler (DPI)
Placebo Comparator: Placebo Two-week washout/run-in period [for patients on a long-acting muscarinic antagonist (LAMA)] followed by a maximum of 36-month double-blind treatment period.	Drug: Placebo; Dose matched placebo, twice per day, oral administration via a multi-dose dry-powder inhaler (DPI)

Outcome Measures

Primary Outcome Measures

1. Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Per Subject Per Year During the First Year of Treatment [12 months]

   The rate (number of events per subject per year) of moderate or severe COPD exacerbations during the first year of treatment based on on-treatment analysis with treatment group, baseline inhaled corticosteroids (ICS) use, baseline COPD severity, history of at least 1 exacerbation in the past year, and smoking status as factors and the log of the exposure time adjusted for the time the subjects experienced exacerbations as an offset variable.

2. Number of Participants With Major Adverse Cardiovascular Event (MACE) - on Study Analysis [At Screening, Treatment period (upto 36 months) and Post-treatment follow-up (PTFU)]

   To assess the cardiovascular (CV) safety of aclidinium bromide on MACEs. The number of subjects with an adjudicated composite MACE with treatment group, baseline CV severity, and smoking status as factors. MACE for the analyses was defined as any adjudicated event which was a composite of the total of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (on-study analysis).

Secondary Outcome Measures

1. Rate of Hospitalizations Due to COPD Exacerbation Per Subject Per Year During the First Year of Treatment- on Treatment Analysis [12 months]

   To assess whether aclidinium bromide reduces moderate or severe COPD exacerbations. The rate of hospitalization (number of events per subject per year) due to COPD exacerbations during the first year of treatment based on on-treatment analysis with treatment group, baseline ICS use, baseline COPD severity, history of at least 1 exacerbation in the past year, and smoking status as factors and the log of the exposure time adjusted for the time the subjects experienced exacerbations as an offset variable.

2. Number of Participants With Major Adverse Cardiovascular Event (MACE) or Other Serious Cardiovascular Events of Interest - On-study Analysis [At Screening, Treatment period (upto 36 months) and Post-treatment follow-up (PTFU)]

   To assess the CV safety of aclidinium bromide on MACEs. The number of subjects with an adjudicated MACE or other serious CV events of interest with treatment group, baseline CV severity, and smoking status as factors. Other serious CV events included events from Cardiac tachyarrhythmias plus preferred terms (PTs) Tachycardia, Heart rate increase, and Palpitation; Cardiac failure; Bradycardia and PTs Sinus arrest and Sinus bradycardia; Conduction defects; Conditions associated with Central nervous system haemorrhages and cerebrovascular accidents; and selected PTs included in the Other ischemic heart disease.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 1. Male or female outpatients ≥ 40 years of age
• 1. Current or former cigarette smokers with a smoking history of at least 10 pack-years
• 1. A diagnosis of stable, moderate to very severe COPD (GOLD, 2015) with a post-bronchodilator FEV < 80% FEV1/forced vital capacity (FVC) ratio < 70%
• 1. Must have at least one of the following 4 criteria:

1. Documented cerebrovascular disease (stroke or transient ischemic attack, carotid stenosis)

2. Documented coronary artery disease (angina, MI, angioplasty/stent/bypass)

3. Documented peripheral vascular disease or history of claudication

4. At least 2 of the following atherothrombotic risk factors as determined by the

PI:

1. Male ≥ 65 years or female ≥ 70 years

2. Diabetes

3. Dyslipidemia

4. Hypertension

5. Waist circumference inches males ≥ 40 in or in females ≥ 38 inches

6. Evidence of renal dysfunction (eGFR < 60) and microalbuminuria (eGFR is based on modification of diet in renal disease [MDRD] equation, microalbuminuria is defined as ≥ 30-300 mcg/mg creatinine on a spot urine or ≥30 mg creatinine on a 24hr urine test)

• 1. Maintained stable respiratory medications for 2 weeks prior to randomization (Appendix II)
• 1. Able to perform pulmonary function test (PFT) maneuvers and follow study procedures
• 1. Women of childbearing potential must have a negative serum β-human chorionic gonadotropin (HCG) pregnancy test at Visit 1A and be practicing medically acceptable method of contraception. Otherwise, female patients should be at least 1 year postmenopausal, surgically sterile (defined as having a hysterectomy or tubal ligation).
• 1. Should understand study procedures and be willing to participate in the study as indicated by signing the ICF

Exclusion Criteria:

• 1. Significant diseases other than COPD or cardiovascular disease (e.g., metastatic cancer) which, in the opinion of the PI, may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient's ability to participate in the study
• 1. Unstable or life threatening cardiovascular disease or COPD as determined by the PI
• 1. Patients with comorbid lung disease such as asthma, cystic fibrosis, bronchiectasis, interstitial lung disease, or pulmonary thromboembolic disease
• 1. Planned lung transplant or lung volume reduction surgery
• 1. Currently treated with a combination of LAMA and LABA/ICS therapy.
• 1. Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within 5 years prior to screening. Patients with treated basal cell and squamous cell (skin) carcinoma are allowed
• 1. Respiratory infection or COPD exacerbation at Screening and/or within 4 weeks prior to screening
• 1. Uncontrolled infection resulting from human immunodeficiency virus (HIV) and/or active hepatitis
• 1. Reported history of drug or alcohol abuse within the past 12 months
• 1. History of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm)
• 1. History of acute urinary retention, treatment refractory benign prostatic hyperplasia (BPH), bladder neck obstruction, or narrow-angle glaucoma (Note: Patients with controlled, stable BPH are not excluded)
• 1. Patients unable to use a multidose DPI or a pressurized metered-dose inhaler
• 1. Treatment with any other investigational drug within 30 days (or 6 half-lives, whichever is longer) before Visit 1A
• 1. Women who are pregnant or breastfeeding
• 1. Use of any prohibited medication listed in Appendix II
• 1. Employee or immediate relative of an employee of AstraZeneca, any of its affiliates or partners, or the study center

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35209
2	Research Site	Birmingham	Alabama	United States	35211
3	Research Site	Birmingham	Alabama	United States	35216
4	Research Site	Birmingham	Alabama	United States	35233
5	Research Site	Birmingham	Alabama	United States	35294
6	Research Site	Florence	Alabama	United States	35630
7	Research Site	Foley	Alabama	United States	36535
8	Research Site	Huntsville	Alabama	United States	35801
9	Research Site	Jasper	Alabama	United States	35501
10	Research Site	Mobile	Alabama	United States	36604
11	Research Site	Tuscaloosa	Alabama	United States	35404
12	Research Site	Chandler	Arizona	United States	85224
13	Research Site	Glendale	Arizona	United States	85306
14	Research Site	Mesa	Arizona	United States	85205
15	Research Site	Peoria	Arizona	United States	85381
16	Research Site	Phoenix	Arizona	United States	85012
17	Research Site	Phoenix	Arizona	United States	85018
18	Research Site	Phoenix	Arizona	United States	85020
19	Research Site	Phoenix	Arizona	United States	85023
20	Research Site	Tucson	Arizona	United States	85710
21	Research Site	Tucson	Arizona	United States	85712
22	Research Site	Tucson	Arizona	United States	85724
23	Research Site	Tucson	Arizona	United States	85741
24	Research Site	Tucson	Arizona	United States	85745
25	Research Site	Hot Springs	Arkansas	United States	71913
26	Research Site	Little Rock	Arkansas	United States	72205
27	Research Site	Little Rock	Arkansas	United States	72209
28	Research Site	Bakersfield	California	United States	93301
29	Research Site	Encinitas	California	United States	92024
30	Research Site	Escondido	California	United States	92025
31	Research Site	Fresno	California	United States	93720
32	Research Site	Gold River	California	United States	95670
33	Research Site	Huntington Beach	California	United States	92647
34	Research Site	La Mirada	California	United States	90638
35	Research Site	Laguna Hills	California	United States	92653
36	Research Site	Lincoln	California	United States	95648
37	Research Site	Loma Linda	California	United States	92357
38	Research Site	Los Angeles	California	United States	90017
39	Research Site	Los Angeles	California	United States	90048
40	Research Site	Los Angeles	California	United States	90073
41	Research Site	North Hollywood	California	United States	91606
42	Research Site	Northridge	California	United States	91324
43	Research Site	Palm Desert	California	United States	92260
44	Research Site	Palm Springs	California	United States	92262
45	Research Site	Paramount	California	United States	90723
46	Research Site	Pismo Beach	California	United States	93449
47	Research Site	Port Hueneme	California	United States	93041
48	Research Site	Poway	California	United States	92064
49	Research Site	Rialto	California	United States	92376
50	Research Site	Riverside	California	United States	92262
51	Research Site	Sacramento	California	United States	95817
52	Research Site	Sacramento	California	United States	95821
53	Research Site	Sacramento	California	United States	95823
54	Research Site	San Diego	California	United States	92117
55	Research Site	San Diego	California	United States	92120
56	Research Site	San Francisco	California	United States	94103
57	Research Site	San Jose	California	United States	95116
58	Research Site	Santa Ana	California	United States	92705
59	Research Site	Santa Monica	California	United States	90404
60	Research Site	Sherman Oaks	California	United States	91403
61	Research Site	Vista	California	United States	92083
62	Research Site	Westminster	California	United States	92683
63	Research Site	Wildomar	California	United States	92595
64	Research Site	Boulder	Colorado	United States	80304
65	Research Site	Centennial	Colorado	United States	80112
66	Research Site	Colorado Springs	Colorado	United States	80907
67	Research Site	Colorado Springs	Colorado	United States	80920
68	Research Site	Golden	Colorado	United States	80401
69	Research Site	Wheat Ridge	Colorado	United States	80033
70	Research Site	Bristol	Connecticut	United States	06010
71	Research Site	Stamford	Connecticut	United States	06902
72	Research Site	Waterbury	Connecticut	United States	06708
73	Research Site	Wilmington	Delaware	United States	19803
74	Research Site	Bay Pines	Florida	United States	33744
75	Research Site	Boynton Beach	Florida	United States	33435
76	Research Site	Brandon	Florida	United States	33511
77	Research Site	Clearwater	Florida	United States	33756
78	Research Site	Clearwater	Florida	United States	33765
79	Research Site	Daytona Beach	Florida	United States	32117
80	Research Site	DeBary	Florida	United States	32713
81	Research Site	DeLand	Florida	United States	32720
82	Research Site	Doral	Florida	United States	33122
83	Research Site	Doral	Florida	United States	33166
84	Research Site	Doral	Florida	United States	33172
85	Research Site	Eustis	Florida	United States	32726
86	Research Site	Gainesville	Florida	United States	32653
87	Research Site	Hialeah	Florida	United States	33012
88	Research Site	Hialeah	Florida	United States	33013
89	Research Site	Hialeah	Florida	United States	33016
90	Research Site	Hollywood	Florida	United States	33021
91	Research Site	Hollywood	Florida	United States	33024
92	Research Site	Homestead	Florida	United States	33030
93	Research Site	Jacksonville	Florida	United States	32209
94	Research Site	Jupiter	Florida	United States	33485
95	Research Site	Kissimmee	Florida	United States	32837
96	Research Site	Kissimmee	Florida	United States	34741
97	Research Site	Leesburg	Florida	United States	34748
98	Research Site	Loxahatchee Groves	Florida	United States	33470
99	Research Site	Maitland	Florida	United States	32751
100	Research Site	Melbourne	Florida	United States	32901
101	Research Site	Miami Beach	Florida	United States	33140
102	Research Site	Miami	Florida	United States	33126
103	Research Site	Miami	Florida	United States	33133
104	Research Site	Miami	Florida	United States	33134
105	Research Site	Miami	Florida	United States	33135
106	Research Site	Miami	Florida	United States	33142
107	Research Site	Miami	Florida	United States	33144
108	Research Site	Miami	Florida	United States	33147
109	Research Site	Miami	Florida	United States	33165
110	Research Site	Miami	Florida	United States	33173
111	Research Site	Miami	Florida	United States	33176
112	Research Site	Miami	Florida	United States	33183
113	Research Site	Miami	Florida	United States	33186
114	Research Site	Naples	Florida	United States	34119
115	Research Site	New Port Richey	Florida	United States	34653
116	Research Site	Ocala	Florida	United States	34471
117	Research Site	Ocala	Florida	United States	34474
118	Research Site	Orange Park	Florida	United States	32073
119	Research Site	Orlando	Florida	United States	32792
120	Research Site	Orlando	Florida	United States	32803
121	Research Site	Orlando	Florida	United States	32811
122	Research Site	Orlando	Florida	United States	32825
123	Research Site	Ormond Beach	Florida	United States	32174
124	Research Site	Oviedo	Florida	United States	32765
125	Research Site	Palmetto Bay	Florida	United States	33157
126	Research Site	Panama City	Florida	United States	32405
127	Research Site	Pembroke Pines	Florida	United States	33024
128	Research Site	Pembroke Pines	Florida	United States	33029
129	Research Site	Pensacola	Florida	United States	32503
130	Research Site	Pinellas Park	Florida	United States	33782
131	Research Site	Plantation	Florida	United States	33322
132	Research Site	Port Charlotte	Florida	United States	33952
133	Research Site	Port Orange	Florida	United States	32127
134	Research Site	Saint Petersburg	Florida	United States	33704
135	Research Site	Saint Petersburg	Florida	United States	33708
136	Research Site	Saint Petersburg	Florida	United States	33711
137	Research Site	Saint Petersburg	Florida	United States	33713
138	Research Site	Santa Rosa Beach	Florida	United States	32459
139	Research Site	Sarasota	Florida	United States	34239
140	Research Site	Sebring	Florida	United States	33870
141	Research Site	Tamarac	Florida	United States	33321
142	Research Site	Tampa	Florida	United States	33613
143	Research Site	Vero Beach	Florida	United States	32960
144	Research Site	Winter Park	Florida	United States	32789
145	Research Site	Atlanta	Georgia	United States	30308
146	Research Site	Atlanta	Georgia	United States	30310
147	Research Site	Atlanta	Georgia	United States	30342
148	Research Site	Blue Ridge	Georgia	United States	30513
149	Research Site	Columbus	Georgia	United States	31904
150	Research Site	Duluth	Georgia	United States	30096
151	Research Site	Johns Creek	Georgia	United States	30097
152	Research Site	Lawrenceville	Georgia	United States	30046
153	Research Site	Marietta	Georgia	United States	30066
154	Research Site	Norcross	Georgia	United States	30092
155	Research Site	Oakwood	Georgia	United States	30566
156	Research Site	Rincon	Georgia	United States	31326
157	Research Site	Savannah	Georgia	United States	31406
158	Research Site	Savannah	Georgia	United States	31419
159	Research Site	Snellville	Georgia	United States	30039
160	Research Site	Snellville	Georgia	United States	30078
161	Research Site	Stockbridge	Georgia	United States	30281
162	Research Site	Woodstock	Georgia	United States	30189
163	Research Site	Eagle	Idaho	United States	83616
164	Research Site	Hayden Lake	Idaho	United States	83835
165	Research Site	Idaho Falls	Idaho	United States	83404
166	Research Site	Meridian	Idaho	United States	83642
167	Research Site	Meridian	Idaho	United States	83646
168	Research Site	Champaign	Illinois	United States	61820
169	Research Site	Chicago	Illinois	United States	60611
170	Research Site	Evanston	Illinois	United States	60201
171	Research Site	Gillespie	Illinois	United States	62033
172	Research Site	Melrose Park	Illinois	United States	60160
173	Research Site	Morton	Illinois	United States	61550
174	Research Site	Normal	Illinois	United States	61761
175	Research Site	North Chicago	Illinois	United States	60064
176	Research Site	O'Fallon	Illinois	United States	62269
177	Research Site	Peoria	Illinois	United States	61602
178	Research Site	Avon	Indiana	United States	46123
179	Research Site	Elwood	Indiana	United States	46036
180	Research Site	Evansville	Indiana	United States	47714
181	Research Site	Evansville	Indiana	United States	47715
182	Research Site	Michigan City	Indiana	United States	46360
183	Research Site	Muncie	Indiana	United States	47303
184	Research Site	Muncie	Indiana	United States	47304
185	Research Site	Valparaiso	Indiana	United States	46383
186	Research Site	Ames	Iowa	United States	50010-3014
187	Research Site	Council Bluffs	Iowa	United States	51503
188	Research Site	Iowa City	Iowa	United States	52242
189	Research Site	Lenexa	Kansas	United States	66219
190	Research Site	Pratt	Kansas	United States	67124
191	Research Site	Topeka	Kansas	United States	66606
192	Research Site	Bowling Green	Kentucky	United States	42101
193	Research Site	Lexington	Kentucky	United States	40503
194	Research Site	Louisville	Kentucky	United States	40202
195	Research Site	Louisville	Kentucky	United States	40218
196	Research Site	Madisonville	Kentucky	United States	42431
197	Research Site	Owensboro	Kentucky	United States	42303
198	Research Site	Covington	Louisiana	United States	70433
199	Research Site	Crowley	Louisiana	United States	70526
200	Research Site	Eunice	Louisiana	United States	70535
201	Research Site	Lake Charles	Louisiana	United States	70601
202	Research Site	Marshall	Louisiana	United States	75670
203	Research Site	Metairie	Louisiana	United States	70006
204	Research Site	New Orleans	Louisiana	United States	70115
205	Research Site	Opelousas	Louisiana	United States	70570
206	Research Site	Shreveport	Louisiana	United States	71105
207	Research Site	Shreveport	Louisiana	United States	71106
208	Research Site	Slidell	Louisiana	United States	70458
209	Research Site	Zachary	Louisiana	United States	70791
210	Research Site	Bangor	Maine	United States	04401
211	Research Site	Biddeford	Maine	United States	04005
212	Research Site	Baltimore	Maryland	United States	21224
213	Research Site	Baltimore	Maryland	United States	21236
214	Research Site	Baltimore	Maryland	United States	21237
215	Research Site	Elkridge	Maryland	United States	21075
216	Research Site	Towson	Maryland	United States	21204
217	Research Site	Fall River	Massachusetts	United States	02720
218	Research Site	Methuen	Massachusetts	United States	01844
219	Research Site	North Dartmouth	Massachusetts	United States	02747
220	Research Site	Pittsfield	Massachusetts	United States	01201
221	Research Site	Bingham Farms	Michigan	United States	48025
222	Research Site	Buckley	Michigan	United States	49620
223	Research Site	Caro	Michigan	United States	48723
224	Research Site	Chesterfield	Michigan	United States	48047
225	Research Site	Farmington Hills	Michigan	United States	48336
226	Research Site	Flint	Michigan	United States	48504
227	Research Site	Rochester	Michigan	United States	48307
228	Research Site	Southfield	Michigan	United States	48034
229	Research Site	Stevensville	Michigan	United States	49127
230	Research Site	Troy	Michigan	United States	48085
231	Research Site	Minneapolis	Minnesota	United States	55402
232	Research Site	Rochester	Minnesota	United States	55905
233	Research Site	Bridgeton	Missouri	United States	63044
234	Research Site	Chesterfield	Missouri	United States	63017
235	Research Site	Columbia	Missouri	United States	65212
236	Research Site	Kansas City	Missouri	United States	64128
237	Research Site	Kansas City	Missouri	United States	64133
238	Research Site	Saint Charles	Missouri	United States	63301
239	Research Site	Saint Louis	Missouri	United States	63128
240	Research Site	Saint Louis	Missouri	United States	63141
241	Research Site	Saint Louis	Missouri	United States	63143
242	Research Site	Springfield	Missouri	United States	65807
243	Research Site	Missoula	Montana	United States	59808
244	Research Site	Bellevue	Nebraska	United States	68005
245	Research Site	Fremont	Nebraska	United States	68025
246	Research Site	Grand Island	Nebraska	United States	68803
247	Research Site	Lincoln	Nebraska	United States	68510
248	Research Site	Lincoln	Nebraska	United States	68516
249	Research Site	Omaha	Nebraska	United States	68114
250	Research Site	Omaha	Nebraska	United States	68124
251	Research Site	Omaha	Nebraska	United States	68130
252	Research Site	Omaha	Nebraska	United States	68134
253	Research Site	Omaha	Nebraska	United States	68144
254	Research Site	Las Vegas	Nevada	United States	89117
255	Research Site	Las Vegas	Nevada	United States	89119
256	Research Site	Las Vegas	Nevada	United States	89123
257	Research Site	Las Vegas	Nevada	United States	89128
258	Research Site	Reno	Nevada	United States	89502
259	Research Site	Sparks	Nevada	United States	89434
260	Research Site	Belvidere	New Jersey	United States	07823
261	Research Site	Bridgewater	New Jersey	United States	08807
262	Research Site	East Brunswick	New Jersey	United States	08816
263	Research Site	Elizabeth	New Jersey	United States	07201
264	Research Site	Haddon Heights	New Jersey	United States	08035
265	Research Site	Summit	New Jersey	United States	07901
266	Research Site	Toms River	New Jersey	United States	08755
267	Research Site	Bronx	New York	United States	10461
268	Research Site	Brooklyn	New York	United States	11229
269	Research Site	Buffalo	New York	United States	14215
270	Research Site	Hopewell Jct	New York	United States	12533
271	Research Site	Jamaica	New York	United States	11435
272	Research Site	New Hyde Park	New York	United States	11040
273	Research Site	New York	New York	United States	10009
274	Research Site	New York	New York	United States	10016
275	Research Site	Syracuse	New York	United States	13210
276	Research Site	Wappingers Falls	New York	United States	12590
277	Research Site	Westfield	New York	United States	14787
278	Research Site	Asheville	North Carolina	United States	28801
279	Research Site	Burlington	North Carolina	United States	27215
280	Research Site	Calabash	North Carolina	United States	28467
281	Research Site	Charlotte	North Carolina	United States	28210
282	Research Site	Charlotte	North Carolina	United States	28262
283	Research Site	Charlotte	North Carolina	United States	28277
284	Research Site	Gastonia	North Carolina	United States	28054
285	Research Site	Greensboro	North Carolina	United States	27405
286	Research Site	Greenville	North Carolina	United States	27834
287	Research Site	Hendersonville	North Carolina	United States	28739
288	Research Site	High Point	North Carolina	United States	27262
289	Research Site	Huntersville	North Carolina	United States	28078
290	Research Site	Lenoir	North Carolina	United States	28645
291	Research Site	Monroe	North Carolina	United States	28110
292	Research Site	Monroe	North Carolina	United States	28112
293	Research Site	Mooresville	North Carolina	United States	28117
294	Research Site	New Bern	North Carolina	United States	28562
295	Research Site	Pinehurst	North Carolina	United States	28374
296	Research Site	Salisbury	North Carolina	United States	28144
297	Research Site	Shelby	North Carolina	United States	28150
298	Research Site	Statesville	North Carolina	United States	28625
299	Research Site	Tabor City	North Carolina	United States	28463
300	Research Site	Whiteville	North Carolina	United States	28472
301	Research Site	Wilmington	North Carolina	United States	28401
302	Research Site	Winston-Salem	North Carolina	United States	27103
303	Research Site	Winston-Salem	North Carolina	United States	27104
304	Research Site	Fargo	North Dakota	United States	58103
305	Research Site	Akron	Ohio	United States	44311
306	Research Site	Canton	Ohio	United States	44718
307	Research Site	Cincinnati	Ohio	United States	45231
308	Research Site	Columbus	Ohio	United States	43207
309	Research Site	Columbus	Ohio	United States	43215
310	Research Site	Dayton	Ohio	United States	45419
311	Research Site	Dayton	Ohio	United States	45439
312	Research Site	Dayton	Ohio	United States	45459
313	Research Site	Delaware	Ohio	United States	43015
314	Research Site	Dublin	Ohio	United States	43016
315	Research Site	Kettering	Ohio	United States	45429
316	Research Site	Maumee	Ohio	United States	43537
317	Research Site	Sylvania	Ohio	United States	43560
318	Research Site	Toledo	Ohio	United States	43608
319	Research Site	Toledo	Ohio	United States	43617
320	Research Site	Norman	Oklahoma	United States	73069
321	Research Site	Oklahoma City	Oklahoma	United States	73103
322	Research Site	Oklahoma City	Oklahoma	United States	73112
323	Research Site	Oklahoma City	Oklahoma	United States	73120
324	Research Site	Tulsa	Oklahoma	United States	74104
325	Research Site	Tulsa	Oklahoma	United States	74136
326	Research Site	Yukon	Oklahoma	United States	73099
327	Research Site	Portland	Oregon	United States	97202
328	Research Site	Portland	Oregon	United States	97210
329	Research Site	Altoona	Pennsylvania	United States	16602
330	Research Site	Beaver	Pennsylvania	United States	15009
331	Research Site	Belle Vernon	Pennsylvania	United States	15012
332	Research Site	Bensalem	Pennsylvania	United States	19020
333	Research Site	Carnegie	Pennsylvania	United States	15106
334	Research Site	Clairton	Pennsylvania	United States	15025
335	Research Site	Downingtown	Pennsylvania	United States	19335
336	Research Site	Erie	Pennsylvania	United States	16508
337	Research Site	Feasterville-Trevose	Pennsylvania	United States	19053
338	Research Site	Jefferson Hills	Pennsylvania	United States	15025
339	Research Site	Levittown	Pennsylvania	United States	19056
340	Research Site	Philadelphia	Pennsylvania	United States	19152
341	Research Site	Pittsburgh	Pennsylvania	United States	15243
342	Research Site	Scottdale	Pennsylvania	United States	15683
343	Research Site	Smithfield	Pennsylvania	United States	15478
344	Research Site	Uniontown	Pennsylvania	United States	15401
345	Research Site	Wyomissing	Pennsylvania	United States	19610
346	Research Site	Yardley	Pennsylvania	United States	19067
347	Research Site	East Providence	Rhode Island	United States	02914
348	Research Site	Anderson	South Carolina	United States	29621
349	Research Site	Charleston	South Carolina	United States	29406
350	Research Site	Charleston	South Carolina	United States	29407
351	Research Site	Charleston	South Carolina	United States	29412
352	Research Site	Columbia	South Carolina	United States	29204
353	Research Site	Easley	South Carolina	United States	29640
354	Research Site	Gaffney	South Carolina	United States	29340
355	Research Site	Gaffney	South Carolina	United States	29341
356	Research Site	Greenville	South Carolina	United States	29605
357	Research Site	Greenville	South Carolina	United States	29615
358	Research Site	Greer	South Carolina	United States	29651
359	Research Site	Hodges	South Carolina	United States	29653
360	Research Site	Indian Land	South Carolina	United States	29707
361	Research Site	Mount Pleasant	South Carolina	United States	29464
362	Research Site	Myrtle Beach	South Carolina	United States	29588
363	Research Site	Orangeburg	South Carolina	United States	29118
364	Research Site	Pelzer	South Carolina	United States	29669
365	Research Site	Rock Hill	South Carolina	United States	29732
366	Research Site	Spartanburg	South Carolina	United States	29302
367	Research Site	Spartanburg	South Carolina	United States	29303
368	Research Site	Summerville	South Carolina	United States	29485
369	Research Site	Union	South Carolina	United States	29379
370	Research Site	Rapid City	South Dakota	United States	57702
371	Research Site	Athens	Tennessee	United States	37303
372	Research Site	Chattanooga	Tennessee	United States	37404
373	Research Site	Fayetteville	Tennessee	United States	37334
374	Research Site	Franklin	Tennessee	United States	37067
375	Research Site	Hendersonville	Tennessee	United States	37075
376	Research Site	Knoxville	Tennessee	United States	37919
377	Research Site	Smyrna	Tennessee	United States	37167
378	Research Site	Spring Hill	Tennessee	United States	37174
379	Research Site	Tullahoma	Tennessee	United States	37388
380	Research Site	Amarillo	Texas	United States	79106
381	Research Site	Arlington	Texas	United States	76014
382	Research Site	Austin	Texas	United States	78759
383	Research Site	Beaumont	Texas	United States	77702
384	Research Site	Boerne	Texas	United States	78006
385	Research Site	Carrollton	Texas	United States	75006
386	Research Site	Corsicana	Texas	United States	75110
387	Research Site	Cypress	Texas	United States	77429
388	Research Site	Dallas	Texas	United States	75220
389	Research Site	Dallas	Texas	United States	75225
390	Research Site	Dallas	Texas	United States	75235
391	Research Site	Dallas	Texas	United States	75246
392	Research Site	Dickinson	Texas	United States	77539
393	Research Site	Duncanville	Texas	United States	75116
394	Research Site	Fort Worth	Texas	United States	76104
395	Research Site	Fort Worth	Texas	United States	76107
396	Research Site	Georgetown	Texas	United States	78626
397	Research Site	Houston	Texas	United States	77011
398	Research Site	Houston	Texas	United States	77043
399	Research Site	Houston	Texas	United States	77058
400	Research Site	Irving	Texas	United States	75039
401	Research Site	North Richland Hills	Texas	United States	76180
402	Research Site	Richardson	Texas	United States	75080
403	Research Site	San Antonio	Texas	United States	78218
404	Research Site	San Antonio	Texas	United States	78258
405	Research Site	Spring	Texas	United States	77379
406	Research Site	Sugar Land	Texas	United States	77478
407	Research Site	Sugar Land	Texas	United States	77479
408	Research Site	Tomball	Texas	United States	77375
409	Research Site	Tyler	Texas	United States	75708
410	Research Site	Waco	Texas	United States	76710
411	Research Site	Webster	Texas	United States	77598
412	Research Site	Midvale	Utah	United States	84047
413	Research Site	Murray	Utah	United States	84107
414	Research Site	Ogden	Utah	United States	84405
415	Research Site	Riverton	Utah	United States	84065
416	Research Site	South Burlington	Vermont	United States	05403
417	Research Site	Abingdon	Virginia	United States	24210
418	Research Site	Manassas	Virginia	United States	20110
419	Research Site	Richmond	Virginia	United States	23114
420	Research Site	Richmond	Virginia	United States	23219
421	Research Site	Richmond	Virginia	United States	23220
422	Research Site	Richmond	Virginia	United States	23225
423	Research Site	Richmond	Virginia	United States	23229
424	Research Site	Bellevue	Washington	United States	98007
425	Research Site	Bellingham	Washington	United States	98225
426	Research Site	Everett	Washington	United States	98208
427	Research Site	Port Orchard	Washington	United States	98366
428	Research Site	Spokane Valley	Washington	United States	99216
429	Research Site	Spokane	Washington	United States	99204
430	Research Site	Tacoma	Washington	United States	98405
431	Research Site	Charleston	West Virginia	United States	25304
432	Research Site	Lewisburg	West Virginia	United States	24901
433	Research Site	Morgantown	West Virginia	United States	26505
434	Research Site	Edmonton	Alberta	Canada	T5A 4L8
435	Research Site	Edmonton	Alberta	Canada	T5J 3S9
436	Research Site	Kamloops	British Columbia	Canada	V2C 5T1
437	Research Site	Kelowna	British Columbia	Canada	V1Y 4N7
438	Research Site	Langley	British Columbia	Canada	V3A 4H9
439	Research Site	Penticton	British Columbia	Canada	V2A 5C8
440	Research Site	West Vancouver	British Columbia	Canada	V7T 1E3
441	Research Site	Winnipeg	Manitoba	Canada	R2V 4W3
442	Research Site	St. John's	Newfoundland and Labrador	Canada	A1A 3R5
443	Research Site	Bridgewater	Nova Scotia	Canada	B4V 3N2
444	Research Site	Halifax	Nova Scotia	Canada	B3K2M5
445	Research Site	Ajax	Ontario	Canada	L1Z 0M1
446	Research Site	Burlington	Ontario	Canada	L7N 3V2
447	Research Site	Cornwall	Ontario	Canada	K6H 4M4
448	Research Site	Dorchester	Ontario	Canada	N0L 1G3
449	Research Site	Hamilton	Ontario	Canada	L8K 3P3
450	Research Site	London	Ontario	Canada	N5Z 1R1
451	Research Site	London	Ontario	Canada	N6A 5G6
452	Research Site	Newmarket	Ontario	Canada	L3Y 5G8
453	Research Site	Sudbury	Ontario	Canada	P3A 1W8
454	Research Site	Sudbury	Ontario	Canada	P3E 6C3
455	Research Site	Thorold	Ontario	Canada	L2V 5A7
456	Research Site	Toronto	Ontario	Canada	M3M 0B2
457	Research Site	Toronto	Ontario	Canada	M4S 1Y2
458	Research Site	Toronto	Ontario	Canada	M5T 3A9
459	Research Site	Toronto	Ontario	Canada	M9V 4B4
460	Research Site	Waterloo	Ontario	Canada	N2J 1C4
461	Research Site	Windsor	Ontario	Canada	N8X 5A6
462	Research Site	Windsor	Ontario	Canada	N8X-5A6
463	Research Site	Longueuil	Quebec	Canada	J4N 1C2
464	Research Site	Montreal	Quebec	Canada	H1M 1B1
465	Research Site	St Charles Borromee	Quebec	Canada	J6E 2B4
466	Research Site	Saskatoon	Saskatchewan	Canada	S7H 5M3
467	Research Site	Quebec		Canada	G1G 3Y8
468	Research Site	Quebec		Canada	G3K 2P8

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Kenneth R. Chapman, MD MSc FRCPC FACP FCCP, GSK-CIHR Research Chair in Respiratory Health Care Delivery,
• Principal Investigator: Robert Wise, MD, Johns Hopkins Bayview Medical Center, Asthma and Allergy Center

Study Documents (Full-Text)

• Study Protocol - Aug 30, 2017
• Statistical Analysis Plan - Oct 23, 2017

More Information

Additional Information:

• Protocol
• Statistical Analysis Plan (SAP)

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01966107
• Other Study ID Numbers: D6560C00002; LAS-MD-45
• First Posted: Oct 21, 2013
• Last Update Posted: Dec 6, 2018
• Last Verified: Nov 1, 2018

• Additional relevant MeSH terms: Pulmonary Disease, Chronic Obstructive; Lung Diseases, Obstructive; Bromides

Study Results

Participant Flow

Recruitment Details	This study was conducted at 522 study centers in North America; 35 centers in Canada and 487 centers in the US. A total of 4000 subjects were planned to be enrolled. A total of 3630 subjects were randomized (1:1) to aclidinium bromide 400 μg twice a day (BID) or placebo BID. Rescue medication (albuterol/salbutamol) was provided for all subjects.
Pre-assignment Detail	Informed consent form was signed; inclusion/exclusion, smoking status, electrocardiogram, pregnancy test, Pulmonary function testing, Chronic obstructive pulmonary disease (COPD) exacerbation were assessed. Out of 3635 subjects, 5 subjects were duplicated, who, in violation of protocol entrance criteria, entered the study more than once.

Arm/Group Title	Aclidinium Bromide	Placebo
Arm/Group Description	Randomized subjects were administered Aclidinium bromide 400 μg BID, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose dry powder inhalation device (DPI). Subjects on a LAMA (long-acting muscarinic antagonist i.e., inhaled anticholinergics) had to washout 2 weeks prior to randomization.	Randomized subjects were administered placebo, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose DPI. Subjects on a LAMA (ie, inhaled anticholinergics) had to washout 2 weeks prior to randomization.
Period Title: Overall Study
STARTED	1812	1818
Full Analysis Set	1791	1798
COMPLETED	1010	937
NOT COMPLETED	802	881

Baseline Characteristics

Arm/Group Title	Aclidinium Bromide	Placebo	Total
Arm/Group Description	Randomized subjects were administered Aclidinium bromide 400 μg BID, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose dry powder inhalation device (DPI). Subjects on a LAMA (long-acting muscarinic antagonist i.e., inhaled anticholinergics) had to washout 2 weeks prior to randomization.	Randomized subjects were administered placebo, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose DPI. Subjects on a LAMA (ie, inhaled anticholinergics) had to washout 2 weeks prior to randomization.	Total of all reporting groups
Overall Participants	1791	1798	3589
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	67.1 (8.5)	67.2 (8.3)	67.2 (8.4)
Age, Customized (Count of Participants)
>=40 - <60 years	340 19%	325 18.1%	665 18.5%
>=60 - <70 years	724 40.4%	725 40.3%	1449 40.4%
>=70 years	727 40.6%	748 41.6%	1475 41.1%
Sex: Female, Male (Count of Participants)
Female	732 40.9%	752 41.8%	1484 41.3%
Male	1059 59.1%	1046 58.2%	2105 58.7%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	5 0.3%	4 0.2%	9 0.3%
Asian	8 0.4%	4 0.2%	12 0.3%
Native Hawaiian or Other Pacific Islander	3 0.2%	0 0%	3 0.1%
Black or African American	165 9.2%	138 7.7%	303 8.4%
White	1603 89.5%	1650 91.8%	3253 90.6%
Other	7 0.4%	2 0.1%	9 0.3%

Outcome Measures

1. Primary Outcome

Title	Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Per Subject Per Year During the First Year of Treatment
Description	The rate (number of events per subject per year) of moderate or severe COPD exacerbations during the first year of treatment based on on-treatment analysis with treatment group, baseline inhaled corticosteroids (ICS) use, baseline COPD severity, history of at least 1 exacerbation in the past year, and smoking status as factors and the log of the exposure time adjusted for the time the subjects experienced exacerbations as an offset variable.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) population consisted of all subjects in the Randomized Population who took at least one dose of the double-blind IP (aclidinium bromide or placebo). Subjects were analyzed according to their randomized treatment.

Arm/Group Title	Aclidinium Bromide	Placebo
Arm/Group Description	Randomized subjects were administered Aclidinium bromide 400 μg BID, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose dry powder inhalation device (DPI). Subjects on a LAMA (long-acting muscarinic antagonist i.e., inhaled anticholinergics) had to washout 2 weeks prior to randomization.	Randomized subjects were administered placebo, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose DPI. Subjects on a LAMA (ie, inhaled anticholinergics) had to washout 2 weeks prior to randomization.
Measure Participants	1791	1798
Number (95% Confidence Interval) [Events per subject per year]	0.44	0.57

2. Secondary Outcome

Title	Rate of Hospitalizations Due to COPD Exacerbation Per Subject Per Year During the First Year of Treatment- on Treatment Analysis
Description	To assess whether aclidinium bromide reduces moderate or severe COPD exacerbations. The rate of hospitalization (number of events per subject per year) due to COPD exacerbations during the first year of treatment based on on-treatment analysis with treatment group, baseline ICS use, baseline COPD severity, history of at least 1 exacerbation in the past year, and smoking status as factors and the log of the exposure time adjusted for the time the subjects experienced exacerbations as an offset variable.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) population consisted of all subjects in the Randomized Population who took at least one dose of the double-blind IP (aclidinium bromide or placebo). Subjects were analyzed according to their randomized treatment.

Arm/Group Title	Aclidinium Bromide	Placebo
Arm/Group Description	Randomized subjects were administered Aclidinium bromide 400 μg BID, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose dry powder inhalation device (DPI). Subjects on a LAMA (long-acting muscarinic antagonist i.e., inhaled anticholinergics) had to washout 2 weeks prior to randomization.	Randomized subjects were administered placebo, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose DPI. Subjects on a LAMA (ie, inhaled anticholinergics) had to washout 2 weeks prior to randomization.
Measure Participants	1791	1798
Number (95% Confidence Interval) [Events per subject per year]	0.07	0.10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aclidinium Bromide, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Negative Binomial Regression model
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.48 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		A rate ratio <1 represents a favorable outcome for aclidinium bromide 400 μg.

3. Secondary Outcome

Title	Number of Participants With Major Adverse Cardiovascular Event (MACE) or Other Serious Cardiovascular Events of Interest - On-study Analysis
Description	To assess the CV safety of aclidinium bromide on MACEs. The number of subjects with an adjudicated MACE or other serious CV events of interest with treatment group, baseline CV severity, and smoking status as factors. Other serious CV events included events from Cardiac tachyarrhythmias plus preferred terms (PTs) Tachycardia, Heart rate increase, and Palpitation; Cardiac failure; Bradycardia and PTs Sinus arrest and Sinus bradycardia; Conduction defects; Conditions associated with Central nervous system haemorrhages and cerebrovascular accidents; and selected PTs included in the Other ischemic heart disease.
Time Frame	At Screening, Treatment period (upto 36 months) and Post-treatment follow-up (PTFU)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) population consisted of all subjects in the Randomized Population who took at least one dose of the double-blind IP (aclidinium bromide or placebo). Subjects were analyzed according to their randomized treatment.

Arm/Group Title	Aclidinium Bromide	Placebo
Arm/Group Description	Randomized subjects were administered Aclidinium bromide 400 μg BID, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose dry powder inhalation device (DPI). Subjects on a LAMA (long-acting muscarinic antagonist i.e., inhaled anticholinergics) had to washout 2 weeks prior to randomization.	Randomized subjects were administered placebo, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose DPI. Subjects on a LAMA (ie, inhaled anticholinergics) had to washout 2 weeks prior to randomization.
Measure Participants	1791	1798
Number of subjects with events	168 9.4%	160 8.9%

4. Primary Outcome

Title	Number of Participants With Major Adverse Cardiovascular Event (MACE) - on Study Analysis
Description	To assess the cardiovascular (CV) safety of aclidinium bromide on MACEs. The number of subjects with an adjudicated composite MACE with treatment group, baseline CV severity, and smoking status as factors. MACE for the analyses was defined as any adjudicated event which was a composite of the total of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (on-study analysis).
Time Frame	At Screening, Treatment period (upto 36 months) and Post-treatment follow-up (PTFU)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) population consisted of all subjects in the Randomized Population who took at least one dose of the double-blind IP (aclidinium bromide or placebo). Subjects were analyzed according to their randomized treatment.

Arm/Group Title	Aclidinium Bromide	Placebo
Arm/Group Description	Randomized subjects were administered Aclidinium bromide 400 μg BID, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose dry powder inhalation device (DPI). Subjects on a LAMA (long-acting muscarinic antagonist i.e., inhaled anticholinergics) had to washout 2 weeks prior to randomization.	Randomized subjects were administered placebo, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose DPI. Subjects on a LAMA (ie, inhaled anticholinergics) had to washout 2 weeks prior to randomization.
Measure Participants	1791	1798
Number of subjects with events	69 3.9%	76 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aclidinium Bromide, Placebo
	Comments	Composite MACE
	Type of Statistical Test	Non-Inferiority
	Comments	Estimate of the hazard ratio and its 95% CI for comparing aclidinium bromide 400 μg versus placebo were derived using the Cox proportional hazard model. A hazard ratio <1 represents a favorable outcome for aclidinium bromide 400 μg.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Any adverse event occurring from the time the informed consent form was signed until 15 days after the last dose of study drug were recorded. Adverse events were collected at Visit 1A for subjects who completed a Visit 0.
Arm/Group Title	Aclidinium Bromide		Placebo
Arm/Group Description	Randomized subjects were administered Aclidinium bromide 400 μg BID, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose dry powder inhalation device (DPI). Subjects on a LAMA (long-acting muscarinic antagonist i.e., inhaled anticholinergics) had to washout 2 weeks prior to randomization.		Randomized subjects were administered placebo, once in the morning and once in the evening (approximately 12 hours apart), via a multi-dose DPI. Subjects on a LAMA (ie, inhaled anticholinergics) had to washout 2 weeks prior to randomization.
All Cause Mortality
	Aclidinium Bromide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	75/1791 (4.2%)		64/1798 (3.6%)
Serious Adverse Events
	Aclidinium Bromide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	409/1791 (22.8%)		356/1798 (19.8%)
Blood and lymphatic system disorders
Iron Deficiency Anaemia	0/1791 (0%)	0	2/1798 (0.1%)	2
Anaemia	6/1791 (0.3%)	6	3/1798 (0.2%)	4
Haemorrhagic Anaemia	1/1791 (0.1%)	1	0/1798 (0%)	0
Microcytic Anaemia	0/1791 (0%)	0	1/1798 (0.1%)	1
Anaemia Of Malignant Disease	0/1791 (0%)	0	1/1798 (0.1%)	2
Leukocytosis	2/1791 (0.1%)	2	2/1798 (0.1%)	2
Immune Thrombocytopenic Purpura	1/1791 (0.1%)	1	0/1798 (0%)	0
Cardiac disorders
Atrioventricular Block Complete	2/1791 (0.1%)	2	4/1798 (0.2%)	5
Atrioventricular Block Second Degree	2/1791 (0.1%)	2	0/1798 (0%)	0
Cardiovascular Disorder	0/1791 (0%)	0	1/1798 (0.1%)	1
Hypertensive Heart Disease	1/1791 (0.1%)	1	0/1798 (0%)	0
Palpitations	0/1791 (0%)	0	1/1798 (0.1%)	1
Cardiomyopathy	1/1791 (0.1%)	1	0/1798 (0%)	0
Ischaemic Cardiomyopathy	1/1791 (0.1%)	1	0/1798 (0%)	0
Stress Cardiomyopathy	0/1791 (0%)	0	1/1798 (0.1%)	1
Arteriosclerosis Coronary Artery	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Coronary Artery Disease	21/1791 (1.2%)	22	8/1798 (0.4%)	8
Coronary Artery Occlusion	2/1791 (0.1%)	2	0/1798 (0%)	0
Coronary Artery Stenosis	2/1791 (0.1%)	2	0/1798 (0%)	0
Cardiac Failure	0/1791 (0%)	0	3/1798 (0.2%)	3
Cardiac Failure Acute	6/1791 (0.3%)	6	6/1798 (0.3%)	6
Cardiac Failure Congestive	21/1791 (1.2%)	24	18/1798 (1%)	19
Cardiogenic Shock	0/1791 (0%)	0	1/1798 (0.1%)	1
Acute Coronary Syndrome	0/1791 (0%)	0	1/1798 (0.1%)	1
Acute Myocardial Infarction	14/1791 (0.8%)	14	12/1798 (0.7%)	12
Angina Pectoris	10/1791 (0.6%)	10	9/1798 (0.5%)	9
Angina Unstable	7/1791 (0.4%)	7	1/1798 (0.1%)	1
Myocardial Infarction	10/1791 (0.6%)	10	13/1798 (0.7%)	13
Pericardial Effusion	1/1791 (0.1%)	1	0/1798 (0%)	0
Arrhythmia	2/1791 (0.1%)	2	2/1798 (0.1%)	2
Bradycardia	3/1791 (0.2%)	3	2/1798 (0.1%)	2
Tachycardia	1/1791 (0.1%)	1	0/1798 (0%)	0
Right Ventricular Failure	2/1791 (0.1%)	2	1/1798 (0.1%)	1
Atrial Fibrillation	24/1791 (1.3%)	30	17/1798 (0.9%)	22
Atrial Flutter	4/1791 (0.2%)	4	3/1798 (0.2%)	3
Atrial Tachycardia	0/1791 (0%)	0	1/1798 (0.1%)	1
Sinus Node Dysfunction	0/1791 (0%)	0	3/1798 (0.2%)	3
Sinus Tachycardia	1/1791 (0.1%)	1	0/1798 (0%)	0
Supraventricular Tachycardia	1/1791 (0.1%)	1	3/1798 (0.2%)	4
Cardiac Arrest	6/1791 (0.3%)	6	4/1798 (0.2%)	4
Cardio-Respiratory Arrest	1/1791 (0.1%)	1	0/1798 (0%)	0
Pulseless Electrical Activity	1/1791 (0.1%)	1	0/1798 (0%)	0
Ventricular Arrhythmia	1/1791 (0.1%)	1	0/1798 (0%)	0
Ventricular Extrasystoles	1/1791 (0.1%)	1	0/1798 (0%)	0
Ventricular Tachycardia	3/1791 (0.2%)	3	2/1798 (0.1%)	2
Ear and labyrinth disorders
Vertigo	0/1791 (0%)	0	1/1798 (0.1%)	1
Vertigo Positional	1/1791 (0.1%)	1	0/1798 (0%)	0
Eye disorders
Retinal Aneurysm	1/1791 (0.1%)	1	0/1798 (0%)	0
Retinal Artery Occlusion	0/1791 (0%)	0	2/1798 (0.1%)	2
Macular Fibrosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Gastrointestinal disorders
Abdominal Hernia	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Pancreatitis	2/1791 (0.1%)	2	3/1798 (0.2%)	4
Pancreatitis Acute	1/1791 (0.1%)	1	3/1798 (0.2%)	3
Gastrointestinal Polyp Haemorrhage	1/1791 (0.1%)	1	0/1798 (0%)	0
Intestinal Polyp	1/1791 (0.1%)	1	0/1798 (0%)	0
Colitis	0/1791 (0%)	0	2/1798 (0.1%)	2
Colitis Ischaemic	2/1791 (0.1%)	2	1/1798 (0.1%)	1
Enterocolitis Haemorrhagic	0/1791 (0%)	0	1/1798 (0.1%)	1
Hiatus Hernia	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Diarrhoea	0/1791 (0%)	0	1/1798 (0.1%)	1
Diverticulum	0/1791 (0%)	0	1/1798 (0.1%)	1
Small Intestinal Obstruction	4/1791 (0.2%)	5	4/1798 (0.2%)	4
Duodenal Ulcer Haemorrhage	1/1791 (0.1%)	1	0/1798 (0%)	0
Faecaloma	1/1791 (0.1%)	1	0/1798 (0%)	0
Gastric Haemorrhage	1/1791 (0.1%)	1	0/1798 (0%)	0
Gastric Ulcer Haemorrhage	1/1791 (0.1%)	2	0/1798 (0%)	0
Gastritis	0/1791 (0%)	0	1/1798 (0.1%)	1
Abdominal Pain	6/1791 (0.3%)	6	0/1798 (0%)	0
Constipation	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Intestinal Mass	0/1791 (0%)	0	1/1798 (0.1%)	1
Intestinal Prolapse	0/1791 (0%)	0	1/1798 (0.1%)	1
Enterovesical Fistula	1/1791 (0.1%)	1	0/1798 (0%)	0
Barrett's Oesophagus	0/1791 (0%)	0	1/1798 (0.1%)	1
Abdominal Discomfort	0/1791 (0%)	0	1/1798 (0.1%)	1
Dysphagia	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Oesophageal Food Impaction	0/1791 (0%)	0	1/1798 (0.1%)	1
Ileus	1/1791 (0.1%)	1	0/1798 (0%)	0
Intestinal Obstruction	3/1791 (0.2%)	3	3/1798 (0.2%)	3
Intestinal Ischaemia	1/1791 (0.1%)	1	0/1798 (0%)	0
Incarcerated Inguinal Hernia	1/1791 (0.1%)	1	0/1798 (0%)	0
Rectal Haemorrhage	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Intestinal Perforation	2/1791 (0.1%)	2	0/1798 (0%)	0
Large Intestinal Obstruction	1/1791 (0.1%)	1	0/1798 (0%)	0
Large Intestinal Stenosis	1/1791 (0.1%)	2	0/1798 (0%)	0
Gastrointestinal Haemorrhage	3/1791 (0.2%)	4	4/1798 (0.2%)	4
Haematemesis	1/1791 (0.1%)	1	0/1798 (0%)	0
Lower Gastrointestinal Haemorrhage	0/1791 (0%)	0	2/1798 (0.1%)	2
Melaena	1/1791 (0.1%)	1	0/1798 (0%)	0
Upper Gastrointestinal Haemorrhage	2/1791 (0.1%)	2	2/1798 (0.1%)	2
Oesophagitis	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Peptic Ulcer	0/1791 (0%)	0	1/1798 (0.1%)	1
Parotid Gland Enlargement	1/1791 (0.1%)	1	0/1798 (0%)	0
General disorders
Asthenia	1/1791 (0.1%)	1	0/1798 (0%)	0
Fatigue	1/1791 (0.1%)	1	0/1798 (0%)	0
Death	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Sudden Death	1/1791 (0.1%)	1	0/1798 (0%)	0
Pyrexia	0/1791 (0%)	0	1/1798 (0.1%)	1
Multiple Organ Dysfunction Syndrome	0/1791 (0%)	0	1/1798 (0.1%)	1
Systemic Inflammatory Response Syndrome	2/1791 (0.1%)	2	1/1798 (0.1%)	1
Mass	0/1791 (0%)	0	1/1798 (0.1%)	1
Oedema Peripheral	0/1791 (0%)	0	1/1798 (0.1%)	1
Chest Pain	5/1791 (0.3%)	5	3/1798 (0.2%)	4
Non-Cardiac Chest Pain	17/1791 (0.9%)	19	8/1798 (0.4%)	10
Hepatobiliary disorders
Cholangitis	1/1791 (0.1%)	1	0/1798 (0%)	0
Cholangitis Acute	1/1791 (0.1%)	2	0/1798 (0%)	0
Cholecystitis	2/1791 (0.1%)	2	1/1798 (0.1%)	1
Cholecystitis Acute	2/1791 (0.1%)	2	0/1798 (0%)	0
Cholelithiasis	1/1791 (0.1%)	1	3/1798 (0.2%)	3
Jaundice Cholestatic	1/1791 (0.1%)	1	0/1798 (0%)	0
Hepatic Cirrhosis	0/1791 (0%)	0	1/1798 (0.1%)	1
Hepatitis Acute	0/1791 (0%)	0	1/1798 (0.1%)	1
Immune system disorders
Drug Hypersensitivity	3/1791 (0.2%)	3	0/1798 (0%)	0
Anaphylactic Reaction	0/1791 (0%)	0	1/1798 (0.1%)	1
Anaphylactic Shock	0/1791 (0%)	0	1/1798 (0.1%)	1
Infections and infestations
Appendicitis	5/1791 (0.3%)	5	0/1798 (0%)	0
Diverticulitis	1/1791 (0.1%)	1	5/1798 (0.3%)	6
Gastroenteritis	0/1791 (0%)	0	2/1798 (0.1%)	2
Infectious Colitis	1/1791 (0.1%)	1	0/1798 (0%)	0
Arthritis Bacterial	1/1791 (0.1%)	1	0/1798 (0%)	0
Bacterial Sepsis	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Breast Cellulitis	0/1791 (0%)	0	1/1798 (0.1%)	1
Catheter Site Cellulitis	0/1791 (0%)	0	1/1798 (0.1%)	1
Cellulitis	14/1791 (0.8%)	16	10/1798 (0.6%)	10
Gangrene	0/1791 (0%)	0	2/1798 (0.1%)	2
Meningitis Bacterial	0/1791 (0%)	0	1/1798 (0.1%)	1
Peritonitis Bacterial	1/1791 (0.1%)	1	0/1798 (0%)	0
Pneumonia Bacterial	3/1791 (0.2%)	3	1/1798 (0.1%)	1
Osteomyelitis	1/1791 (0.1%)	1	0/1798 (0%)	0
Breast Abscess	0/1791 (0%)	0	1/1798 (0.1%)	1
Campylobacter Colitis	0/1791 (0%)	0	1/1798 (0.1%)	1
Extradural Abscess	1/1791 (0.1%)	1	0/1798 (0%)	0
Clostridium Difficile Colitis	2/1791 (0.1%)	2	0/1798 (0%)	0
Clostridium Difficile Infection	0/1791 (0%)	0	1/1798 (0.1%)	1
Pseudomembranous Colitis	0/1791 (0%)	0	1/1798 (0.1%)	1
Tongue Abscess	1/1791 (0.1%)	1	0/1798 (0%)	0
Tooth Abscess	1/1791 (0.1%)	1	0/1798 (0%)	0
Escherichia Urinary Tract Infection	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Lower Respiratory Tract Infection Fungal	0/1791 (0%)	0	1/1798 (0.1%)	1
Herpes Zoster	0/1791 (0%)	0	1/1798 (0.1%)	1
Localised Infection	0/1791 (0%)	0	1/1798 (0.1%)	1
Post Procedural Infection	0/1791 (0%)	0	1/1798 (0.1%)	1
Bacterial Disease Carrier	0/1791 (0%)	0	1/1798 (0.1%)	1
H1n1 Influenza	0/1791 (0%)	0	1/1798 (0.1%)	1
Influenza	4/1791 (0.2%)	4	6/1798 (0.3%)	6
Pneumonia Influenzal	0/1791 (0%)	0	1/1798 (0.1%)	1
Atypical Pneumonia	0/1791 (0%)	0	1/1798 (0.1%)	1
Bronchitis	2/1791 (0.1%)	2	2/1798 (0.1%)	2
Pneumonia	66/1791 (3.7%)	78	58/1798 (3.2%)	61
Muscle Abscess	0/1791 (0%)	0	1/1798 (0.1%)	1
Measles	0/1791 (0%)	0	1/1798 (0.1%)	1
Bacteraemia	0/1791 (0%)	0	1/1798 (0.1%)	1
Pulmonary Sepsis	1/1791 (0.1%)	1	0/1798 (0%)	0
Sepsis	12/1791 (0.7%)	12	14/1798 (0.8%)	14
Septic Shock	1/1791 (0.1%)	1	0/1798 (0%)	0
Urosepsis	1/1791 (0.1%)	1	0/1798 (0%)	0
Staphylococcal Abscess	0/1791 (0%)	0	1/1798 (0.1%)	1
Staphylococcal Sepsis	0/1791 (0%)	0	1/1798 (0.1%)	1
Cellulitis Streptococcal	0/1791 (0%)	0	1/1798 (0.1%)	1
Pneumonia Pneumococcal	1/1791 (0.1%)	1	0/1798 (0%)	0
Pneumonia Streptococcal	0/1791 (0%)	0	1/1798 (0.1%)	1
Streptococcal Bacteraemia	1/1791 (0.1%)	1	0/1798 (0%)	0
Tuberculosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Acute Sinusitis	0/1791 (0%)	0	1/1798 (0.1%)	1
Cystitis	1/1791 (0.1%)	1	0/1798 (0%)	0
Pyelonephritis	2/1791 (0.1%)	2	0/1798 (0%)	0
Urinary Tract Infection	5/1791 (0.3%)	5	9/1798 (0.5%)	10
Gastroenteritis Viral	2/1791 (0.1%)	2	0/1798 (0%)	0
Pneumonia Viral	1/1791 (0.1%)	1	0/1798 (0%)	0
Injury, poisoning and procedural complications
Splenic Rupture	0/1791 (0%)	0	2/1798 (0.1%)	3
Coronary Vascular Graft Stenosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Peripheral Arterial Reocclusion	0/1791 (0%)	0	1/1798 (0.1%)	1
Subarachnoid Haemorrhage	3/1791 (0.2%)	3	0/1798 (0%)	0
Subdural Haematoma	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Open Globe Injury	0/1791 (0%)	0	1/1798 (0.1%)	1
Ankle Fracture	1/1791 (0.1%)	1	0/1798 (0%)	0
Femoral Neck Fracture	5/1791 (0.3%)	5	3/1798 (0.2%)	3
Femur Fracture	3/1791 (0.2%)	3	1/1798 (0.1%)	1
Fibula Fracture	0/1791 (0%)	0	2/1798 (0.1%)	2
Forearm Fracture	1/1791 (0.1%)	1	0/1798 (0%)	0
Hip Fracture	5/1791 (0.3%)	5	3/1798 (0.2%)	3
Humerus Fracture	1/1791 (0.1%)	1	0/1798 (0%)	0
Lower Limb Fracture	0/1791 (0%)	0	1/1798 (0.1%)	1
Patella Fracture	0/1791 (0%)	0	1/1798 (0.1%)	1
Radial Head Dislocation	1/1791 (0.1%)	1	0/1798 (0%)	0
Radius Fracture	1/1791 (0.1%)	1	0/1798 (0%)	0
Tibia Fracture	0/1791 (0%)	0	2/1798 (0.1%)	2
Ulna Fracture	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Muscle Strain	0/1791 (0%)	0	1/1798 (0.1%)	1
Periprosthetic Fracture	0/1791 (0%)	0	1/1798 (0.1%)	1
Nerve Root Injury Lumbar	0/1791 (0%)	0	1/1798 (0.1%)	1
Fall	8/1791 (0.4%)	8	3/1798 (0.2%)	3
Fat Embolism	1/1791 (0.1%)	1	0/1798 (0%)	0
Road Traffic Accident	6/1791 (0.3%)	6	2/1798 (0.1%)	2
Anaemia Postoperative	0/1791 (0%)	0	1/1798 (0.1%)	1
Post Procedural Haematoma	0/1791 (0%)	0	1/1798 (0.1%)	1
Post Procedural Haemorrhage	0/1791 (0%)	0	1/1798 (0.1%)	1
Intentional Overdose	0/1791 (0%)	0	1/1798 (0.1%)	1
Overdose	0/1791 (0%)	0	1/1798 (0.1%)	1
Pubis Fracture	0/1791 (0%)	0	1/1798 (0.1%)	1
Alcohol Poisoning	0/1791 (0%)	0	2/1798 (0.1%)	2
Carbon Monoxide Poisoning	0/1791 (0%)	0	1/1798 (0.1%)	1
Accidental Overdose	0/1791 (0%)	0	1/1798 (0.1%)	1
Osteoradionecrosis	0/1791 (0%)	0	1/1798 (0.1%)	1
Radiation Dysphagia	1/1791 (0.1%)	1	0/1798 (0%)	0
Radiation Mucositis	1/1791 (0.1%)	1	0/1798 (0%)	0
Head Injury	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Laceration	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Cervical Vertebral Fracture	0/1791 (0%)	0	1/1798 (0.1%)	1
Fractured Sacrum	1/1791 (0.1%)	1	0/1798 (0%)	0
Lumbar Vertebral Fracture	0/1791 (0%)	0	1/1798 (0.1%)	1
Spinal Compression Fracture	1/1791 (0.1%)	1	0/1798 (0%)	0
Spinal Fracture	1/1791 (0.1%)	1	0/1798 (0%)	0
Rib Fracture	4/1791 (0.2%)	4	1/1798 (0.1%)	1
Sternal Fracture	0/1791 (0%)	0	1/1798 (0.1%)	1
Investigations
Electrocardiogram Abnormal	0/1791 (0%)	0	1/1798 (0.1%)	1
Heart Rate Decreased	0/1791 (0%)	0	1/1798 (0.1%)	1
Hepatic Enzyme Increased	1/1791 (0.1%)	1	0/1798 (0%)	0
Troponin Increased	2/1791 (0.1%)	2	2/1798 (0.1%)	2
Influenza A Virus Test Positive	0/1791 (0%)	0	1/1798 (0.1%)	1
Metabolism and nutrition disorders
Diabetes Mellitus Inadequate Control	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Diabetic Ketoacidosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Gout	1/1791 (0.1%)	1	0/1798 (0%)	0
Electrolyte Imbalance	0/1791 (0%)	0	1/1798 (0.1%)	1
Hypertriglyceridaemia	0/1791 (0%)	0	1/1798 (0.1%)	1
Obesity	1/1791 (0.1%)	1	0/1798 (0%)	0
Hyperglycaemia	5/1791 (0.3%)	5	3/1798 (0.2%)	3
Hypoglycaemia	3/1791 (0.2%)	3	6/1798 (0.3%)	7
Lactic Acidosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Acidosis	0/1791 (0%)	0	1/1798 (0.1%)	1
Hypokalaemia	0/1791 (0%)	0	3/1798 (0.2%)	4
Hyponatraemia	4/1791 (0.2%)	4	2/1798 (0.1%)	2
Dehydration	4/1791 (0.2%)	4	2/1798 (0.1%)	2
Fluid Overload	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Musculoskeletal and connective tissue disorders
Bursitis	1/1791 (0.1%)	1	0/1798 (0%)	0
Hip Deformity	0/1791 (0%)	0	1/1798 (0.1%)	1
Intervertebral Disc Degeneration	0/1791 (0%)	0	3/1798 (0.2%)	3
Intervertebral Disc Protrusion	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Muscular Weakness	1/1791 (0.1%)	1	2/1798 (0.1%)	3
Back Pain	6/1791 (0.3%)	7	4/1798 (0.2%)	4
Musculoskeletal Chest Pain	4/1791 (0.2%)	5	0/1798 (0%)	0
Musculoskeletal Pain	0/1791 (0%)	0	1/1798 (0.1%)	1
Pain In Extremity	0/1791 (0%)	0	1/1798 (0.1%)	1
Osteoarthritis	6/1791 (0.3%)	6	1/1798 (0.1%)	1
Cervical Spinal Stenosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Lumbar Spinal Stenosis	4/1791 (0.2%)	4	1/1798 (0.1%)	1
Spinal Column Stenosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Spondylolisthesis	0/1791 (0%)	0	1/1798 (0.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anal Cancer	1/1791 (0.1%)	1	0/1798 (0%)	0
B-Cell Lymphoma	0/1791 (0%)	0	1/1798 (0.1%)	1
Bladder Cancer	2/1791 (0.1%)	2	3/1798 (0.2%)	3
Bladder Transitional Cell Carcinoma	1/1791 (0.1%)	1	0/1798 (0%)	0
Breast Cancer Female	0/1791 (0%)	0	4/1798 (0.2%)	4
Invasive Ductal Breast Carcinoma	0/1791 (0%)	0	2/1798 (0.1%)	2
Carcinoid Tumour Of The Stomach	1/1791 (0.1%)	1	0/1798 (0%)	0
Adenocarcinoma Of Colon	1/1791 (0.1%)	1	0/1798 (0%)	0
Colon Cancer	0/1791 (0%)	0	1/1798 (0.1%)	1
Dermatofibrosarcoma Protuberans	1/1791 (0.1%)	1	0/1798 (0%)	0
Hepatic Cancer	2/1791 (0.1%)	2	0/1798 (0%)	0
Hepatic Cancer Metastatic	2/1791 (0.1%)	2	0/1798 (0%)	0
Hepatocellular Carcinoma	1/1791 (0.1%)	1	0/1798 (0%)	0
Hepatic Adenoma	1/1791 (0.1%)	1	0/1798 (0%)	0
Hodgkin's Disease	0/1791 (0%)	0	1/1798 (0.1%)	1
Laryngeal Cancer	1/1791 (0.1%)	1	0/1798 (0%)	0
Benign Salivary Gland Neoplasm	0/1791 (0%)	0	1/1798 (0.1%)	1
Squamous Cell Carcinoma Of The Tongue	0/1791 (0%)	0	1/1798 (0.1%)	1
Lymphoma	0/1791 (0%)	0	1/1798 (0.1%)	1
Meningioma Benign	1/1791 (0.1%)	1	0/1798 (0%)	0
Mesothelioma	0/1791 (0%)	0	1/1798 (0.1%)	1
Metastases To Central Nervous System	0/1791 (0%)	0	1/1798 (0.1%)	1
Adenocarcinoma	1/1791 (0.1%)	1	0/1798 (0%)	0
Metastatic Neoplasm	0/1791 (0%)	0	1/1798 (0.1%)	1
Metastatic Squamous Cell Carcinoma	1/1791 (0.1%)	1	0/1798 (0%)	0
Squamous Cell Carcinoma	4/1791 (0.2%)	4	1/1798 (0.1%)	1
Squamous Cell Carcinoma Of Head And Neck	1/1791 (0.1%)	1	0/1798 (0%)	0
Non-Hodgkin's Lymphoma	1/1791 (0.1%)	1	0/1798 (0%)	0
Lung Adenocarcinoma	5/1791 (0.3%)	5	2/1798 (0.1%)	2
Lung Adenocarcinoma Stage Iii	0/1791 (0%)	0	1/1798 (0.1%)	1
Lung Adenocarcinoma Stage Iv	1/1791 (0.1%)	1	0/1798 (0%)	0
Non-Small Cell Lung Cancer	1/1791 (0.1%)	1	6/1798 (0.3%)	6
Non-Small Cell Lung Cancer Stage Iiib	1/1791 (0.1%)	1	0/1798 (0%)	0
Squamous Cell Carcinoma Of Lung	6/1791 (0.3%)	6	5/1798 (0.3%)	5
Oesophageal Adenocarcinoma	0/1791 (0%)	0	1/1798 (0.1%)	1
Oesophageal Carcinoma	1/1791 (0.1%)	1	0/1798 (0%)	0
Cancer Pain	0/1791 (0%)	0	1/1798 (0.1%)	1
Pancreatic Carcinoma	1/1791 (0.1%)	1	0/1798 (0%)	0
Prostate Cancer	4/1791 (0.2%)	4	2/1798 (0.1%)	2
Clear Cell Renal Cell Carcinoma	1/1791 (0.1%)	1	0/1798 (0%)	0
Renal Cell Carcinoma	2/1791 (0.1%)	2	0/1798 (0%)	0
Lung Neoplasm	1/1791 (0.1%)	1	0/1798 (0%)	0
Respiratory Tract Neoplasm	0/1791 (0%)	0	1/1798 (0.1%)	1
Lung Cancer Metastatic	1/1791 (0.1%)	1	0/1798 (0%)	0
Lung Neoplasm Malignant	6/1791 (0.3%)	6	3/1798 (0.2%)	3
Small Cell Lung Cancer	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Malignant Melanoma	2/1791 (0.1%)	2	0/1798 (0%)	0
Basal Cell Carcinoma	0/1791 (0%)	0	1/1798 (0.1%)	1
Bowen's Disease	1/1791 (0.1%)	1	0/1798 (0%)	0
Transitional Cell Carcinoma	2/1791 (0.1%)	2	1/1798 (0.1%)	1
Vaginal Cancer Stage 0	1/1791 (0.1%)	1	0/1798 (0%)	0
Nervous system disorders
Basal Ganglia Haemorrhage	1/1791 (0.1%)	1	0/1798 (0%)	0
Carotid Artery Occlusion	1/1791 (0.1%)	1	0/1798 (0%)	0
Cerebral Haemorrhage	0/1791 (0%)	0	2/1798 (0.1%)	2
Cerebral Infarction	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Cerebrovascular Accident	9/1791 (0.5%)	9	4/1798 (0.2%)	4
Embolic Stroke	0/1791 (0%)	0	1/1798 (0.1%)	1
Haemorrhage Intracranial	0/1791 (0%)	0	1/1798 (0.1%)	1
Ischaemic Stroke	1/1791 (0.1%)	1	5/1798 (0.3%)	5
Lacunar Infarction	1/1791 (0.1%)	1	0/1798 (0%)	0
Carotid Artery Disease	1/1791 (0.1%)	1	0/1798 (0%)	0
Carotid Artery Stenosis	4/1791 (0.2%)	4	5/1798 (0.3%)	6
Balance Disorder	0/1791 (0%)	0	1/1798 (0.1%)	1
Syncope	7/1791 (0.4%)	7	2/1798 (0.1%)	2
Encephalopathy	0/1791 (0%)	0	1/1798 (0.1%)	1
Toxic Encephalopathy	0/1791 (0%)	0	2/1798 (0.1%)	2
Generalised Tonic-Clonic Seizure	0/1791 (0%)	0	1/1798 (0.1%)	1
Tension Headache	0/1791 (0%)	0	1/1798 (0.1%)	1
Lumbar Radiculopathy	0/1791 (0%)	0	1/1798 (0.1%)	1
Sciatica	0/1791 (0%)	0	1/1798 (0.1%)	1
Hemianopia Homonymous	0/1791 (0%)	0	1/1798 (0.1%)	1
Dizziness	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Presyncope	0/1791 (0%)	0	1/1798 (0.1%)	1
Paraesthesia	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Paraplegia	1/1791 (0.1%)	1	0/1798 (0%)	0
Neuropathy Peripheral	1/1791 (0.1%)	1	0/1798 (0%)	0
Seizure	1/1791 (0.1%)	1	2/1798 (0.1%)	4
Radicular Pain	0/1791 (0%)	0	1/1798 (0.1%)	1
Radiculopathy	1/1791 (0.1%)	1	0/1798 (0%)	0
Spinal Claudication	0/1791 (0%)	0	1/1798 (0.1%)	1
Transient Ischaemic Attack	8/1791 (0.4%)	9	5/1798 (0.3%)	5
Product Issues
Device Malfunction	1/1791 (0.1%)	1	0/1798 (0%)	0
Psychiatric disorders
Anxiety	2/1791 (0.1%)	2	0/1798 (0%)	0
Confusional State	0/1791 (0%)	0	1/1798 (0.1%)	1
Delirium	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Depression	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Major Depression	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Mental Status Changes	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Alcohol Abuse	0/1791 (0%)	0	1/1798 (0.1%)	1
Drug Use Disorder	0/1791 (0%)	0	2/1798 (0.1%)	2
Substance Use Disorder	1/1791 (0.1%)	1	0/1798 (0%)	0
Renal and urinary disorders
Pollakiuria	1/1791 (0.1%)	1	0/1798 (0%)	0
Urinary Retention	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Bladder Diverticulum	0/1791 (0%)	0	1/1798 (0.1%)	1
Bladder Necrosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Renal Mass	1/1791 (0.1%)	1	0/1798 (0%)	0
Acute Kidney Injury	7/1791 (0.4%)	7	7/1798 (0.4%)	7
Chronic Kidney Disease	0/1791 (0%)	0	2/1798 (0.1%)	2
Renal Failure	5/1791 (0.3%)	5	0/1798 (0%)	0
Renal Impairment	2/1791 (0.1%)	2	0/1798 (0%)	0
Nephrolithiasis	2/1791 (0.1%)	2	0/1798 (0%)	0
Hydronephrosis	0/1791 (0%)	0	1/1798 (0.1%)	1
Renal Artery Thrombosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Haematuria	1/1791 (0.1%)	1	0/1798 (0%)	0
Proteinuria	0/1791 (0%)	0	1/1798 (0.1%)	1
Reproductive system and breast disorders
Breast Mass	1/1791 (0.1%)	1	0/1798 (0%)	0
Prostatomegaly	1/1791 (0.1%)	1	0/1798 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/1791 (0.1%)	2	2/1798 (0.1%)	2
Pickwickian Syndrome	1/1791 (0.1%)	1	0/1798 (0%)	0
Respiratory Arrest	2/1791 (0.1%)	2	0/1798 (0%)	0
Respiratory Distress	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Sleep Apnoea Syndrome	0/1791 (0%)	0	1/1798 (0.1%)	1
Asthma	0/1791 (0%)	0	1/1798 (0.1%)	1
Chronic Obstructive Pulmonary Disease	1/1791 (0.1%)	1	3/1798 (0.2%)	3
Hypercapnia	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Hypoxia	4/1791 (0.2%)	5	1/1798 (0.1%)	1
Respiratory Acidosis	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Haemoptysis	0/1791 (0%)	0	3/1798 (0.2%)	3
Pneumonitis	0/1791 (0%)	0	1/1798 (0.1%)	1
Pulmonary Fibrosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Bronchopleural Fistula	0/1791 (0%)	0	1/1798 (0.1%)	1
Pleurisy	0/1791 (0%)	0	1/1798 (0.1%)	1
Haemothorax	1/1791 (0.1%)	1	0/1798 (0%)	0
Pleural Effusion	4/1791 (0.2%)	4	2/1798 (0.1%)	3
Pneumothorax	3/1791 (0.2%)	3	5/1798 (0.3%)	5
Pneumothorax Spontaneous	3/1791 (0.2%)	3	3/1798 (0.2%)	4
Pulmonary Hypertension	1/1791 (0.1%)	1	0/1798 (0%)	0
Acute Pulmonary Oedema	0/1791 (0%)	0	1/1798 (0.1%)	1
Pulmonary Oedema	2/1791 (0.1%)	2	0/1798 (0%)	0
Pulmonary Embolism	4/1791 (0.2%)	4	4/1798 (0.2%)	4
Acute Respiratory Failure	16/1791 (0.9%)	20	17/1798 (0.9%)	18
Chronic Respiratory Failure	1/1791 (0.1%)	1	0/1798 (0%)	0
Respiratory Failure	9/1791 (0.5%)	9	11/1798 (0.6%)	13
Pulmonary Mass	2/1791 (0.1%)	2	2/1798 (0.1%)	2
Thoracic Haemorrhage	0/1791 (0%)	0	1/1798 (0.1%)	1
Skin and subcutaneous tissue disorders
Angioedema	1/1791 (0.1%)	1	2/1798 (0.1%)	2
Stasis Dermatitis	1/1791 (0.1%)	1	0/1798 (0%)	0
Erythema	0/1791 (0%)	0	1/1798 (0.1%)	1
Subcutaneous Emphysema	1/1791 (0.1%)	1	0/1798 (0%)	0
Skin Ulcer	0/1791 (0%)	0	1/1798 (0.1%)	1
Vascular disorders
Accelerated Hypertension	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Hypertensive Crisis	0/1791 (0%)	0	2/1798 (0.1%)	2
Aortic Aneurysm	4/1791 (0.2%)	4	2/1798 (0.1%)	2
Aortic Aneurysm Rupture	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Aortic Occlusion	1/1791 (0.1%)	1	0/1798 (0%)	0
Aortic Stenosis	2/1791 (0.1%)	2	2/1798 (0.1%)	2
Leriche Syndrome	0/1791 (0%)	0	1/1798 (0.1%)	1
Hypovolaemic Shock	0/1791 (0%)	0	1/1798 (0.1%)	1
Shock	1/1791 (0.1%)	1	0/1798 (0%)	0
Haematoma	1/1791 (0.1%)	1	0/1798 (0%)	0
Thrombosis	0/1791 (0%)	0	1/1798 (0.1%)	1
Arteriosclerosis	0/1791 (0%)	0	1/1798 (0.1%)	1
Peripheral Venous Disease	2/1791 (0.1%)	2	0/1798 (0%)	0
Peripheral Artery Aneurysm	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Deep Vein Thrombosis	5/1791 (0.3%)	5	2/1798 (0.1%)	2
Pelvic Venous Thrombosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Thrombophlebitis Superficial	1/1791 (0.1%)	1	0/1798 (0%)	0
Peripheral Vascular Disorder	3/1791 (0.2%)	4	2/1798 (0.1%)	2
Intermittent Claudication	2/1791 (0.1%)	2	1/1798 (0.1%)	4
Peripheral Arterial Occlusive Disease	3/1791 (0.2%)	5	3/1798 (0.2%)	3
Peripheral Artery Occlusion	0/1791 (0%)	0	2/1798 (0.1%)	2
Peripheral Ischaemia	1/1791 (0.1%)	1	1/1798 (0.1%)	3
Hypertension	3/1791 (0.2%)	3	2/1798 (0.1%)	2
Hypotension	8/1791 (0.4%)	8	1/1798 (0.1%)	1
Orthostatic Hypotension	1/1791 (0.1%)	1	1/1798 (0.1%)	1
Arteriovenous Fistula	1/1791 (0.1%)	1	0/1798 (0%)	0
Vena Cava Thrombosis	1/1791 (0.1%)	1	0/1798 (0%)	0
Other (Not Including Serious) Adverse Events
	Aclidinium Bromide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1105/1791 (61.7%)		1065/1798 (59.2%)
Blood and lymphatic system disorders
Anaemia	40/1791 (2.2%)	40	38/1798 (2.1%)	39
Cardiac disorders
Atrial Fibrillation	27/1791 (1.5%)	30	40/1798 (2.2%)	44
Gastrointestinal disorders
Diarrhoea	58/1791 (3.2%)	62	62/1798 (3.4%)	67
Constipation	60/1791 (3.4%)	65	53/1798 (2.9%)	53
Gastrooesophageal Reflux Disease	38/1791 (2.1%)	38	23/1798 (1.3%)	23
Nausea	77/1791 (4.3%)	83	57/1798 (3.2%)	64
General disorders
Oedema Peripheral	48/1791 (2.7%)	54	61/1798 (3.4%)	70
Infections and infestations
Bronchitis	70/1791 (3.9%)	85	74/1798 (4.1%)	92
Pneumonia	46/1791 (2.6%)	51	52/1798 (2.9%)	57
Sinusitis	65/1791 (3.6%)	87	63/1798 (3.5%)	73
Upper Respiratory Tract Infection	86/1791 (4.8%)	104	101/1798 (5.6%)	117
Urinary Tract Infection	90/1791 (5%)	122	84/1798 (4.7%)	104
Viral Upper Respiratory Tract Infection	78/1791 (4.4%)	95	67/1798 (3.7%)	77
Musculoskeletal and connective tissue disorders
Arthralgia	50/1791 (2.8%)	53	45/1798 (2.5%)	51
Muscle Spasms	40/1791 (2.2%)	44	34/1798 (1.9%)	36
Back Pain	69/1791 (3.9%)	72	54/1798 (3%)	57
Musculoskeletal Pain	28/1791 (1.6%)	31	38/1798 (2.1%)	40
Pain In Extremity	35/1791 (2%)	37	38/1798 (2.1%)	41
Nervous system disorders
Headache	57/1791 (3.2%)	74	65/1798 (3.6%)	84
Dizziness	44/1791 (2.5%)	46	42/1798 (2.3%)	45
Psychiatric disorders
Anxiety	34/1791 (1.9%)	35	39/1798 (2.2%)	42
Respiratory, thoracic and mediastinal disorders
Dyspnoea	48/1791 (2.7%)	52	70/1798 (3.9%)	74
Cough	67/1791 (3.7%)	71	62/1798 (3.4%)	66
Vascular disorders
Hypertension	64/1791 (3.6%)	66	56/1798 (3.1%)	60

Limitations/Caveats

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

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