Safety Study of Arformoterol Tartrate Inhalation Solution in Chronic Obstructive Pulmonary Disease (COPD) Subjects

• Sponsor: Sunovion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00909779
• Collaborator: (none)
• Enrollment: 841
• Locations: 73
• Arms: 2
• Duration (Months): 36
• Patients Per Site: 11.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a multi-center study to evaluate the long-term safety of arformoterol 15 mcg twice daily (BID) in the treatment of subjects with moderate-to-severe COPD. Study participation will consist of a total of 6 visits over approximately 1 year.

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

Detailed Description

This is a multi-center, double-blind, randomized, placebo-controlled, parallel-group, outpatient, safety study to evaluate the long-term safety of arformoterol 15 mcg twice daily (BID) in the treatment of subjects with moderate-to-severe COPD. The administration of arformoterol in subjects with moderate to severe COPD will not result in a meaningfully greater incidence of respiratory death and COPD exacerbation -related hospitalizations compared to placebo (nebulized saline and non-long-acting beta2-agonist [LABA] COPD standard of care treatments). This study was previously posted by Sepracor Inc. In October 2009, Sepracor Inc. was acquired by Dainippon Sumitomo Pharma., and in October 2010, Sepracor Inc's name was changed to Sunovion Pharmaceuticals Inc.

Study Design

• Study Type: Interventional
• Actual Enrollment: 841 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Large Simple Safety Study of Arformoterol Tartrate Inhalation Solution in Subjects With Chronic Obstructive Pulmonary Disease
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arformoterol 15 mcg twice daily Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.	Drug: Arformoterol; Arformoterol Tartrate Inhalation Solution 15 mcg twice daily (BID) for a duration of one year; Other Names: Brovana
Placebo Comparator: Placebo twice daily Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.	Drug: Placebo; Placebo inhalation solution, twice daily (BID) for a duration of one year.

Outcome Measures

Primary Outcome Measures

1. Time From Randomization to Respiratory Death or First COPD Exacerbation Related Hospitalization (Whichever Occurs First). [0-12 months]

   COPD exacerbation: an increase in COPD symptoms that necessitated any change in baseline medication (bronchodilators,anti-inflammatory agents, antibiotics, supplemental oxygen therapy, etc.).Hospitalization: any inpatient admission or any emergency department visit > 24 hours in duration. Hospice was considered hospitalization.COPD exacerbation related hospitalization: hospitalization that was due to 1) COPD exacerbation or 2) a COPD exacerbation preceded, or occurred concomitantly with the onset of, the event for which the subject was hospitalized.Respiratory-related death: For each death the Primary Investigator designated a 'probable cause', which was the primary condition that precipitated the terminal events that were the immediate cause of death. If a probable cause could not be ascertained, the cause of death was considered 'UNKNOWN'. Cause other than 'UNKNOWN' was categorized as either respiratory or non-respiratory. Deaths of 'UNKNOWN' cause were counted as primary events.

Secondary Outcome Measures

1. The Incidence of Protocol Defined COPD Exacerbations. [0-12 months]

   A protocol-defined exacerbation of COPD was defined as an increase in respiratory symptoms (classically, increased shortness of breath, increased sputum production, and/or increased sputum purulence) that necessitates any change in baseline medication other than bronchodilators (e.g., anti-inflammatory agents, antibiotics, supplemental oxygen therapy, etc) or causes the subject to require additional medical attention (i.e., emergency room visit or hospitalization).

2. The Incidence of All Cause Mortality [0-12 months]

   Survival status at the end of the study will be determined for each subject. The proportion of subjects dead and the annual event rate will be summarized by treatment.

3. The Incidence of Treatment Emergent AEs [0-12 months]

   TEAEs were defined as: 1) adverse events that occurred on or after the date of first dose of study medication, 2) adverse events with a missing start date and a stop date on or after the date of first does of study medication, or 3) adverse events with both a missing start and stop date. The frequency and percentage of subjects with TEAEs were summarized. At each level of summarization, a subject was counted only once for each AE he/she experienced within that level. The percentage of subjects having had at least 1 AE at each level was calculated.

4. SGRQ: Mean Change From Baseline in Total Score [Baseline and on treatment at months 3, 6 and 12 (or early termination)]

   The SGRQ assessed health status and consisted of 3 component scores (Symptoms, Activity, and Impacts) as well as a total score. Items were scored in accordance with the developer's guidelines. Scores were expressed as a percentage of overall impairment, where 100 represented worst possible health status and 0 indicated best possible health status. The SGRQ was assessed pre-dose at baseline, months 3, 6 and 12 or the end of study (EOS). Visit 2 was defined as baseline. A change from baseline in the Total Score of ≥ 4 units is considered the minimal clinically important difference (MCID) for SGRQ.

5. FEV1: Mean Change From Baseline [Baseline and on treatments at months 3, 6, 9 and 12 (or early termination)]

   FEV1 was measured at Visit 1 (screening), pre- and post-albuterol administration for reversibility testing, pre-dose at baseline, months 3, 6, 9 and 12/EOS. The best FEV1 from at least 3 acceptable maneuvers was recorded. Study baseline was defined as the Visit 2 pre-dose value. If the Visit 2 pre-dose value was missing, the last FEV1 value obtained prior to first treatment was used for baseline.

6. Percent Predicted FEV1: Mean Change From Baseline [Baseline and on treatments at months 3, 6, 9 and 12 (or early termination)]

   Percent predicted FEV1: measured FEV1 as a percent of the "predicted values" for the patients of similar characteristics (height, age, sex, and sometimes race and weight). Best FEV1 percent predicted was measured at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS, as described for FEV1.

7. Forced Vital Capacity (FVC): Mean Change From Baseline [Baseline and on treatment at months 3, 6, 9 and 12 (or early termination)]

   Forced Vital capacity: the volume of air that can forcibly be blown out after full inspiration. Best FVC was measured at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS. The best FVC from at least 3 acceptable maneuvers was recorded.

8. Inspiratory Capacity (IC): Mean Change From Baseline [Baseline and on treatment at months 3, 6, 9 and 12 (or early termination)]

   IC: the total amount of air that can be drawn into the lungs after normal expiration. IC was measured pre- and post-albuterol administration at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS. IC maneuvers were done in triplicate. The mean of all recorded IC values was used for each subject at each time point. Study baseline was defined as the Visit 2 pre-dose value. If the Visit 2 pre-dose value was missing, the last IC value obtained prior to first treatment dose was used for baseline.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subject must give written informed consent, including privacy authorization as well as adherence to concomitant medication withholding periods, prior to participation.

• Females considered not of childbearing potential must be surgically sterile (total hysterectomy, bilateral salpingo oophorectomy, or tubal ligation) or post-menopausal, which is defined as a complete cessation of menstruation for at least 1 year.

• Male and female subjects must be at least 40 years old at the time of consent.

• Subjects must have a pre-established, documented primary clinical diagnosis of non-asthmatic COPD or are referred for diagnosis of non-asthmatic COPD.

• Subjects must have a baseline FEV1 of ≤50% predicted volume at Visits 1 and 2 (pre-dose).

• Subjects must have a FEV1 >0.50 L at either Visit 1 or 2 (pre-dose).

• Subject's respiratory status must be clinically stable.

• Subjects must have a FEV1/forced vital capacity (FVC) ratio of ≤70% at either Visit 1 or 2 (pre-dose).

• Subjects must have had at least 1 COPD exacerbation within the last year (defined as initiation or an increase in the dose of oral steroids or antibiotics for the treatment of COPD).

• Subjects must have a ≥15 pack-year smoking history and a baseline breathlessness severity grade of ≥2 (Modified Medical Research Council [MMRC] Dyspnea Scale Score) at Visit 2.

• Female subjects ≤65 years of age must have a negative serum pregnancy test conducted at Visit 1 prior to randomization. Females of childbearing potential must be using an acceptable method of birth control.

• Subjects' overall health must be sufficiently stable to complete the study requirements based on the screening physical examination (defined as the absence of any clinically relevant abnormalities), medical history, 12-lead ECG, and clinical laboratory values (hematology, serum chemistry and urinalysis), and vital signs (heart rate, respiratory rate, and blood pressure) that have been conducted within 30 days of Visit 2 (randomization). If any of the hematology, chemistry, or urinalysis results are not within the laboratory's reference range, then the subject can be included only if the investigator judges the deviations to be not clinically significant.

• Subjects must have a minimum blood pressure of 105/60 mmHg and a minimum resting pulse of 50 bpm at Screening Visit 1. Subjects who do not meet these criteria at Screening Visit 1 must meet the criteria on the first day of dosing (Day 1) in order to be eligible for the study. Subjects with a medical condition which causes low blood pressure or low heart rate, but, in the opinion of the Principal Investigator or designee the medical condition could resolve, may be rescreened when the condition is resolved.

• Subjects must be willing and able to complete all study questionnaires and logs reliably.

• Subjects must be willing and able to comply with study procedures and visit schedule.

• Subjects must have sufficient understanding of English to complete all questionnaires and logs.

Exclusion Criteria:

• Female subjects who are pregnant or lactating.

• Subjects with a history of asthma, with the exception of asthma diagnosed in childhood.

• Subjects with a blood eosinophil count >5% of total white blood cell count.

• Subjects with a febrile illness within 3 days before Screening.

• Subjects with a malignant neoplasm other than non melanomatous basal cell skin cancer. Subjects with a history of malignancy who have been cancer free for 5 years or more may be enrolled.

• Subjects who are currently using disallowed medications or will be unable to complete the medication washout periods. Subjects taking a prohibited concurrent medication which requires a washout of >30 days may be rescreened when the washout of the prohibited concurrent medication has been met.

• Subjects with life threatening/unstable respiratory status, including upper or lower respiratory tract infection, within the previous 30 days prior to screening.

• Subjects who have had a change in dose or type of any medications for COPD within 2 weeks prior to the screening visit. Subjects not on a stable dose of COPD medications may be rescreened after being on a stable dose for at least 14 days

• Subjects with a chest x ray taken ≤3 months prior to screening that suggests a diagnosis other than COPD (eg, diagnostic of pneumonia, other infection, atelectasis, or pneumothorax or other active/ongoing pulmonary conditions). If there is no chest x ray taken ≤3 months prior to screening, or if recent results are unavailable for review, a chest x ray must be performed prior to visit 2. Subjects with a medical condition that caused the abnormal finding, but, in the opinion of the Principal Investigator or designee the medical condition could resolve, may be rescreened when the condition is resolved

• Subjects with a positive urine drug test during screening.

• Subjects with a known history of alcohol abuse may be enrolled in the study if the subject's current alcohol use does not exceed more than 3 alcoholic beverages per day.

• Subjects whose schedule or travel prevents the completion of all required visits.

• Subjects who are scheduled for inpatient hospitalization or elective surgery (inpatient or outpatient) during the trial. Subjects may be rescreened when the condition is resolved.

• Subjects have participated in an investigational drug study and/or any COPD interventional trial within 30 days prior to screening or who are currently participating in another investigational drug study or COPD interventional trial.

• Subjects with a history of allergic reaction to the study medication or any components of the study medications.

• Subjects who are study site staff members or relatives of study site staff members directly involved in this study.

• Subjects with clinically significant cardiac, (Functional Class III and IV; Objective Class C and D by New York Heart Association [NYHA] Functional Classification),hepatic, renal, gastrointestinal, endocrine, metabolic, neurologic, or psychiatric disorder that may interfere with successful completion of this protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jefferson Clinic	Birmingham	Alabama	United States	25233
2	Alabama Clinical Therapeutic, LLC	Birmingham	Alabama	United States	35235
3	Achieve Clinical Research	Brimingham	Alabama	United States	35209
4	Jasper Summit Research, LLC	Jasper	Alabama	United States	35501
5	Chest Critical Care Consultants	Anaheim	California	United States	92801
6	California Research Medical Group	Fullerton	California	United States	92835
7	Integrated Research Group	Riverside	California	United States	92506
8	Quality Control Research Inc.	Roseville	California	United States	95661
9	Sockolov and Sockolov APC	Sacramento	California	United States	95825
10	Centers for Clinical Trials of Sacremento	Sacremento	California	United States	95823
11	Institute of HealthCare Assessment, Inc.	San Diego	California	United States	92120
12	National Jewish Health	Denver	Colorado	United States	80206
13	Southeast Clinical Research	Chiefland	Florida	United States	32626
14	Tampa Bay Medical Research Inc.	Clearwater	Florida	United States	33761
15	Clinical Research of West Florida, Inc.	Clearwater	Florida	United States	33765
16	Avail Clinical Research	DeLand	Florida	United States	32720
17	The Lung Clinic, P.A.	Kissimmee	Florida	United States	34741
18	DCT	Orlando	Florida	United States	32806
19	Clinical Research of West Florida	Tampa	Florida	United States	33603
20		Canton	Georgia	United States	30114
21	Southeast Regional Research Group	Columbus	Georgia	United States	31904
22	Atlanta Pharmaceutical Research	Decatur	Georgia	United States	30033
23	Wellstar Marietta Pulmonary Medicine	Marietta	Georgia	United States	30060
24	Southeast Regional Research Group	Rincon	Georgia	United States	31326
25	Medisphere Medical Research Center	Evansville	Indiana	United States	47714
26	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
27	Kentucky Lung Clinic	Hazard	Kentucky	United States	41701
28	Bendel Medical Research Center, LLC	Lafayette	Louisiana	United States	70503
29	ClinSite LLC	Ann Arbor	Michigan	United States	48106
30	Clinical Research Institute Inc.	Minneapolis	Minnesota	United States	55402
31	Midwest Chest Consultants	St. Charles	Missouri	United States	63301
32	C.A.R.E. Clinical Research	St. Louis	Missouri	United States	63141
33	Comprehensive Clinical Research	Berlin	New Jersey	United States	08009
34	Delaware Valley Clinical Research	Cherry Hill	New Jersey	United States	08003
35	New York Pulmonary and Clinical Care Associates, PC	New York	New York	United States	10016
36	ENT & Allergy Associates	Newburgh	New York	United States	12550
37	Rochester Clinical Research	Rochester	New York	United States	14609
38	AAIR Research Center	Rochester	New York	United States	14618
39	American Health Research Inc.	Charlotte	North Carolina	United States	28207
40	Piedmont Medical Research	Winston-Salem	North Carolina	United States	27103
41	DayStar Clinical Research, Inc.	Akron	Ohio	United States	44313
42	Bernstein Clinical Research Center	Cincinnati	Ohio	United States	45231
43	Clinical Research Institute of Southern Oregon, PC	Medford	Oregon	United States	97504
44	Allergy Associates Research Center	Portland	Oregon	United States	97216
45	Arcuri Clinical Research, LLC	Philadelphia	Pennsylvania	United States	19142
46	Biomedical Research Alliance at Hypertension and Nephrology	Pawtucket	Rhode Island	United States	02860
47	Omega Medical Research	Warwick	Rhode Island	United States	02886
48	Lowcountry Lung & Critical Care, PA	Charleston	South Carolina	United States	29406
49	Neem Research Group, Inc.	Columbia	South Carolina	United States	29201
50	Gaffney Pharmaceutical Research	Gaffney	South Carolina	United States	29340
51	Greenville Pharmaceutical Research	Greenville	South Carolina	United States	29615
52	Upstate Pharmaceutical Research	Greenville	South Carolina	United States	29615
53	Mountain View Clinical Research, Inc.	Greer	South Carolina	United States	29651
54	S. Carolina Pharmaceutical Research	Spartanburg	South Carolina	United States	29303
55	CU Pharmaceutical Research	Union	South Carolina	United States	29379
56	Allergy Associates	Knoxville	Tennessee	United States	37909
57	Volunteer Research Group	Knoxville	Tennessee	United States	37920
58	DCT	Arlington	Texas	United States	76014
59	Baylor College of Medicine, Clinical Studies Unit, Ben Taub General Hospital	Houston	Texas	United States	77030
60	VAMC	Houston	Texas	United States	77030
61	Kingwood Research Institute, LLC	Kingwood	Texas	United States	77339
62	Physician PrimeCare Research	San Antonio	Texas	United States	78212
63	Diagnostics Research Group	San Antonio	Texas	United States	78229
64	DCT	Sugar Land	Texas	United States	77878
65	SouthEast Research Institute	Webster	Texas	United States	77598
66	National Clinical Resources, Inc.	Provo	Utah	United States	84604
67	Utah Clinical Trials LLC	Salt Lake City	Utah	United States	84107
68	Charlottesville Medical Research Inc.	Charlottesville	Virginia	United States	22911
69	Manassas Clinical Research Center	Manassas	Virginia	United States	20110
70	Dominion Medical Associates	Richmond	Virginia	United States	23219
71	Pulmonary Associates of Richmond Inc.	Richmond	Virginia	United States	23225
72	Pulmonary Associates of Richmond, Inc.	Richmond	Virginia	United States	23229
73	Pulmonary Consultants, PLLC	Tacoma	Washington	United States	98405

Sponsors and Collaborators

• Sunovion

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sunovion
• ClinicalTrials.gov Identifier: NCT00909779
• Other Study ID Numbers: 091-080
• First Posted: May 28, 2009
• Last Update Posted: Nov 11, 2013
• Last Verified: Sep 1, 2013

• Keywords provided by Sunovion: Chronic obstructive pulmonary disease (COPD); respiratory; long-acting beta agonist (LABA)
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Formoterol Fumarate

Study Results

Participant Flow

Arm/Group Title	Placebo Twice Daily	Arformoterol 15 Mcg Twice Daily
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.
Period Title: Overall Study
STARTED	421	420
COMPLETED	211	255
NOT COMPLETED	210	165

Baseline Characteristics

Arm/Group Title	Placebo Comparator: Placebo Twice Daily	Experimental: Arformoterol 15 Mcg Twice Daily	Total
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.	Total of all reporting groups
Overall Participants	421	420	841
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	222 52.7%	204 48.6%	426 50.7%
>=65 years	199 47.3%	216 51.4%	415 49.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.3 (9.5)	64.2 (9.3)	63.8 (9.4)
Sex/Gender, Customized (participants) [Number]
Female	178 42.3%	183 43.6%	361 42.9%
Male	243 57.7%	236 56.2%	479 57%
Undifferentiated	0 0%	1 0.2%	1 0.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	15 3.6%	9 2.1%	24 2.9%
Not Hispanic or Latino	402 95.5%	411 97.9%	813 96.7%
Unknown or Not Reported	4 1%	0 0%	4 0.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.2%	1 0.2%	2 0.2%
Asian	2 0.5%	2 0.5%	4 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	43 10.2%	45 10.7%	88 10.5%
White	374 88.8%	372 88.6%	746 88.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.2%	0 0%	1 0.1%
Region of Enrollment (participants) [Number]
United States	421 100%	420 100%	841 100%
Number of COPD exacerbations in last year (Number of occurrences) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Number of occurrences]	0.8 (1.1)	1.0 (1.4)	0.9 (1.3)
FEV1 (Liter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Liter]	1.178 (0.487)	1.176 (0.482)	1.177 (0.485)
Percent predicted FEV1 (%) (Percentage (%)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage (%)]	39.4 (13.9)	39.7 (13.2)	39.5 (13.5)
Baseline smoking status (Current) [Number]
Current	218	214	432
Former	203	206	409
Number of pack-years smoked (Pack-years) [Number]
≥ 15 - < 25	41 (9.7)	40 (9.5)	81 (9.6)
≥ 25 - < 30	36 (8.6)	29 (6.9)	65 (7.7)
≥ 30	344 (81.7)	351 (83.6)	695 (82.6)
Baseline Oral/Inhaled Corticosteroid Use (participants) [Number]
No	202 (48.0) 48%	202 (48.1) 48.1%	404 (48.0) 48%
Yes	219 (52.0) 52%	218 (51.9) 51.9%	437 (52.0) 52%
Baseline Oxygen Therapy Use (participants) [Number]
No	330 (78.4) 78.4%	334 (79.5) 79.5%	664 (79.0) 79%
Yes	91 (21.6) 21.6%	86 (20.5) 20.5%	177 (21.0) 21%

Outcome Measures

1. Primary Outcome

Title	Time From Randomization to Respiratory Death or First COPD Exacerbation Related Hospitalization (Whichever Occurs First).
Description	COPD exacerbation: an increase in COPD symptoms that necessitated any change in baseline medication (bronchodilators,anti-inflammatory agents, antibiotics, supplemental oxygen therapy, etc.).Hospitalization: any inpatient admission or any emergency department visit > 24 hours in duration. Hospice was considered hospitalization.COPD exacerbation related hospitalization: hospitalization that was due to 1) COPD exacerbation or 2) a COPD exacerbation preceded, or occurred concomitantly with the onset of, the event for which the subject was hospitalized.Respiratory-related death: For each death the Primary Investigator designated a 'probable cause', which was the primary condition that precipitated the terminal events that were the immediate cause of death. If a probable cause could not be ascertained, the cause of death was considered 'UNKNOWN'. Cause other than 'UNKNOWN' was categorized as either respiratory or non-respiratory. Deaths of 'UNKNOWN' cause were counted as primary events.
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.

Arm/Group Title	Experimental: Arformoterol 15 Mcg Twice Daily	Placebo
Arm/Group Description	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.	Placebo twice daily
Measure Participants	420	421
Measure Subjects with Primary Event	63	40
Mean (Standard Deviation) [Days]	155.0 (91.2)	171.7 (98.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental: Arformoterol 15 Mcg Twice Daily
	Comments	The null hypothesis is: There is 40% or higher excess risk of the primary events in the arformoterol group relative to placebo (a constant hazard ratio of 1.4). The primary analysis was a Cox proportional hazards regression model, with treatment group, baseline smoking status, sex, age, BMI, and baseline FEV1 as covariates. The hazard ratio and 90% two-sided confidence interval for the hazard ratio (adjusted for the interim analysis) comparing arformoterol to placebo were estimated.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The study was powered under a one-sided alternative hypothesis, in which arformoterol is superior to placebo, with a hazard ratio of 0.80 or less. To achieve 80% power, it was necessary to observe 86 total events for the primary endpoint adjusted for interim analysis. Assuming an annual event proportion of 17.3% in the placebo group and 30% lost to follow-up, we anticipated to randomize approximately 900 subjects (450 per arm). The non-inferiority margin for the hazard ratio is 1.4.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.606
	Confidence Interval	(2-Sided) 95%; 0.425 to 0.864
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was calculated as arformoterol vs. placebo.

2. Secondary Outcome

Title	The Incidence of Protocol Defined COPD Exacerbations.
Description	A protocol-defined exacerbation of COPD was defined as an increase in respiratory symptoms (classically, increased shortness of breath, increased sputum production, and/or increased sputum purulence) that necessitates any change in baseline medication other than bronchodilators (e.g., anti-inflammatory agents, antibiotics, supplemental oxygen therapy, etc) or causes the subject to require additional medical attention (i.e., emergency room visit or hospitalization).
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.

Arm/Group Title	Placebo Comparator: Placebo Twice Daily	Experimental: Arformoterol 15 Mcg Twice Daily
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatent of COPD symptoms.	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.
Measure Participants	421	420
Overall	132 31.4%	122 29%
1 COPD event	72 17.1%	71 16.9%
2 COPD events	34 8.1%	29 6.9%
3 or more COPD events	26 6.2%	22 5.2%

3. Secondary Outcome

Title	The Incidence of All Cause Mortality
Description	Survival status at the end of the study will be determined for each subject. The proportion of subjects dead and the annual event rate will be summarized by treatment.
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.

Arm/Group Title	Placebo Comparator: Placebo Twice Daily	Experimental: Arformoterol 15 Mcg Twice Daily
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatent of COPD symptoms.	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.
Measure Participants	421	420
Number [participants]	10 2.4%	12 2.9%

4. Secondary Outcome

Title	The Incidence of Treatment Emergent AEs
Description	TEAEs were defined as: 1) adverse events that occurred on or after the date of first dose of study medication, 2) adverse events with a missing start date and a stop date on or after the date of first does of study medication, or 3) adverse events with both a missing start and stop date. The frequency and percentage of subjects with TEAEs were summarized. At each level of summarization, a subject was counted only once for each AE he/she experienced within that level. The percentage of subjects having had at least 1 AE at each level was calculated.
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.

Arm/Group Title	Placebo Comparator: Placebo Twice Daily	Experimental: Arformoterol 15 Mcg Twice Daily
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatent of COPD symptoms.	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.
Measure Participants	421	420
Number [participants]	287 68.2%	306 72.9%

5. Secondary Outcome

Title	SGRQ: Mean Change From Baseline in Total Score
Description	The SGRQ assessed health status and consisted of 3 component scores (Symptoms, Activity, and Impacts) as well as a total score. Items were scored in accordance with the developer's guidelines. Scores were expressed as a percentage of overall impairment, where 100 represented worst possible health status and 0 indicated best possible health status. The SGRQ was assessed pre-dose at baseline, months 3, 6 and 12 or the end of study (EOS). Visit 2 was defined as baseline. A change from baseline in the Total Score of ≥ 4 units is considered the minimal clinically important difference (MCID) for SGRQ.
Time Frame	Baseline and on treatment at months 3, 6 and 12 (or early termination)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.

Arm/Group Title	Placebo Comparator: Placebo Twice Daily	Experimental: Arformoterol 15 Mcg Twice Daily
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatent of COPD symptoms.	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.
Measure Participants	421	420
Month 3 (n=276,308)	-1.544 (0.609)	-3.876 (0.575)
Month 6 (n=233,287)	-1.855 (0.746)	-4.054 (0.679)
Month 12 (n=199,236)	-2.673 (0.800)	-4.796 (0.735)
EOS (n=375,379)	-0.587 (0.616)	-3.231 (0.613)

6. Secondary Outcome

Title	FEV1: Mean Change From Baseline
Description	FEV1 was measured at Visit 1 (screening), pre- and post-albuterol administration for reversibility testing, pre-dose at baseline, months 3, 6, 9 and 12/EOS. The best FEV1 from at least 3 acceptable maneuvers was recorded. Study baseline was defined as the Visit 2 pre-dose value. If the Visit 2 pre-dose value was missing, the last FEV1 value obtained prior to first treatment was used for baseline.
Time Frame	Baseline and on treatments at months 3, 6, 9 and 12 (or early termination)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.

Arm/Group Title	Placebo Comparator: Placebo Twice Daily	Experimental: Arformoterol 15 Mcg Twice Daily
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatent of COPD symptoms.	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.
Measure Participants	421	420
Month 3 (n=289,331)	0.027 (0.018)	0.093 (0.016)
Month 6 (n=248,300)	0.036 (0.023)	0.090 (0.021)
Month 9 (n=223,268)	0.048 (0.019)	0.092 (0.018)
Month 12 (n=206,253)	0.020 (0.020)	0.059 (0.018)
EOS (n=380,391)	0.047 (0.016)	0.072 (0.016)

7. Secondary Outcome

Title	Percent Predicted FEV1: Mean Change From Baseline
Description	Percent predicted FEV1: measured FEV1 as a percent of the "predicted values" for the patients of similar characteristics (height, age, sex, and sometimes race and weight). Best FEV1 percent predicted was measured at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS, as described for FEV1.
Time Frame	Baseline and on treatments at months 3, 6, 9 and 12 (or early termination)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.

Arm/Group Title	Placebo Comparator: Placebo Twice Daily	Experimental: Arformoterol 15 Mcg Twice Daily
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatent of COPD symptoms.	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.
Measure Participants	421	420
Month 3 (n=289,331)	1.410 (0.533)	3.480 (0.498)
Month 6 (n=248,300)	1.768 (0.648)	3.460 (0.594)
Month 9 (n=223,268)	2.606 (0.626)	3.651 (0.576)
Month 12 (n=206,252)	1.678 (0.642)	2.662 (0.586)
EOS (n=380,391)	2.156 (0.493)	2.936 (0.486)

8. Secondary Outcome

Title	Forced Vital Capacity (FVC): Mean Change From Baseline
Description	Forced Vital capacity: the volume of air that can forcibly be blown out after full inspiration. Best FVC was measured at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS. The best FVC from at least 3 acceptable maneuvers was recorded.
Time Frame	Baseline and on treatment at months 3, 6, 9 and 12 (or early termination)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.

Arm/Group Title	Placebo Comparator: Placebo Twice Daily	Experimental: Arformoterol 15 Mcg Twice Daily
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatent of COPD symptoms.	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.
Measure Participants	421	420
Month 3 (n=289,331)	0.039 (0.024)	0.139 (0.022)
Month 6 (n=248,300)	0.056 (0.031)	0.120 (0.028)
Month 9 (n=223,268)	0.049 (0.029)	0.139 (0.027)
Month 12 (n=206,253)	0.040 (0.029)	0.088 (0.027)
EOS (n=380,391)	0.056 (0.022)	0.102 (0.022)

9. Secondary Outcome

Title	Inspiratory Capacity (IC): Mean Change From Baseline
Description	IC: the total amount of air that can be drawn into the lungs after normal expiration. IC was measured pre- and post-albuterol administration at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS. IC maneuvers were done in triplicate. The mean of all recorded IC values was used for each subject at each time point. Study baseline was defined as the Visit 2 pre-dose value. If the Visit 2 pre-dose value was missing, the last IC value obtained prior to first treatment dose was used for baseline.
Time Frame	Baseline and on treatment at months 3, 6, 9 and 12 (or early termination)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.

Arm/Group Title	Placebo Comparator: Placebo Twice Daily	Experimental: Arformoterol 15 Mcg Twice Daily
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatent of COPD symptoms.	Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.
Measure Participants	421	420
Month 3 (n=284,320)	0.030 (0.023)	0.054 (0.021)
Month 6 (n=243,298)	-0.011 (0.026)	0.067 (0.024)
Month 9 (n=218,258)	0.046 (0.029)	0.096 (0.027)
Month 12 (n=199,246)	0.004 (0.029)	0.035 (0.027)
EOS (n=374,384)	0.031 (0.022)	0.058 (0.021)

Adverse Events

Time Frame	1 year
Arm/Group Title	Placebo Comparator: Placebo Twice Daily		Experimental: Arformoterol 15 Mcg Twice Daily
Arm/Group Description	Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.		Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms.
All Cause Mortality
	Placebo Comparator: Placebo Twice Daily		Experimental: Arformoterol 15 Mcg Twice Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo Comparator: Placebo Twice Daily		Experimental: Arformoterol 15 Mcg Twice Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	95/421 (22.6%)		86/420 (20.5%)
Blood and lymphatic system disorders
Anemia	1/421 (0.2%)	1	1/420 (0.2%)	1
Leukocytosis	1/421 (0.2%)	1	0/420 (0%)	0
Cardiac disorders
Acute coronary syndrome	1/421 (0.2%)	1	0/420 (0%)	0
Acute myocardial infarction	1/421 (0.2%)	1	1/420 (0.2%)	1
Angina pectoris	1/421 (0.2%)	1	3/420 (0.7%)	3
Angina Unstable	0/421 (0%)	0	1/420 (0.2%)	1
Atrial fibrillation	2/421 (0.5%)	2	3/420 (0.7%)	3
Atrioventricular block complete	1/421 (0.2%)	1	0/420 (0%)	0
Bundle branch block right	1/421 (0.2%)	1	0/420 (0%)	0
Cardiac failure congestive	3/421 (0.7%)	3	2/420 (0.5%)	2
Cardio-respiratory arrest	0/421 (0%)	0	2/420 (0.5%)	2
Cardiomyopathy	1/421 (0.2%)	1	0/420 (0%)	0
Corpulmonale	0/421 (0%)	0	1/420 (0.2%)	1
Coronary artery disease	0/421 (0%)	0	3/420 (0.7%)	3
Myocardial infarction	2/421 (0.5%)	2	1/420 (0.2%)	1
Myocardial ischaemia	0/421 (0%)	0	1/420 (0.2%)	1
Ear and labyrinth disorders
Vertigo	1/421 (0.2%)	1	1/420 (0.2%)	2
Eye disorders
Iridocyclitis	0/421 (0%)	0	1/420 (0.2%)	1
Retinal artery occlusion	1/421 (0.2%)	1	0/420 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/421 (0.2%)	1	0/420 (0%)	0
Abdominal pain upper	1/421 (0.2%)	1	0/420 (0%)	0
Barrett's oesophagus	0/421 (0%)	0	1/420 (0.2%)	1
Colonic polyp	1/421 (0.2%)	1	0/420 (0%)	0
Diverticular perforation	0/421 (0%)	0	1/420 (0.2%)	1
Enteritis	1/421 (0.2%)	1	0/420 (0%)	0
Gastric ulcer	1/421 (0.2%)	1	1/420 (0.2%)	1
Gastric ulcer haemorrhage	0/421 (0%)	0	1/420 (0.2%)	1
Gastritis erosive	0/421 (0%)	0	1/420 (0.2%)	1
Gastrointestinal haemorrhage	2/421 (0.5%)	2	2/420 (0.5%)	2
Gastrooesophageal reflux disease	1/421 (0.2%)	1	0/420 (0%)	0
Hiatus hernia	0/421 (0%)	0	1/420 (0.2%)	1
Intestinal perforation	0/421 (0%)	0	1/420 (0.2%)	1
Pancreatitis acute	0/421 (0%)	0	1/420 (0.2%)	1
Rectal haemorrhage	1/421 (0.2%)	1	0/420 (0%)	0
Small intestinal obstruction	1/421 (0.2%)	1	0/420 (0%)	0
General disorders
Non-cardiac chest pain	1/421 (0.2%)	1	3/420 (0.7%)	3
Oedema peripheral	0/421 (0%)	0	1/420 (0.2%)	1
Hepatobiliary disorders
Cholecystitis	0/421 (0%)	0	1/420 (0.2%)	1
Gallbladder perforation	1/421 (0.2%)	1	0/420 (0%)	0
Infections and infestations
Abscess limb	1/421 (0.2%)	1	0/420 (0%)	0
Bronchitis	9/421 (2.1%)	10	3/420 (0.7%)	4
Bronchopneumonia	0/421 (0%)	0	1/420 (0.2%)	1
Cellulitis	1/421 (0.2%)	1	1/420 (0.2%)	1
Clostridial infection	0/421 (0%)	0	1/420 (0.2%)	1
Clostridium difficile colitis	0/421 (0%)	0	1/420 (0.2%)	1
Diverticulitis	1/421 (0.2%)	1	0/420 (0%)	0
Gastritis fungal	1/421 (0.2%)	1	0/420 (0%)	0
Gastroenteritis bacteria	0/421 (0%)	0	1/420 (0.2%)	1
Influenza	1/421 (0.2%)	1	0/420 (0%)	0
Osteomyelitis	0/421 (0%)	0	1/420 (0.2%)	1
Osteomy	0/421 (0%)	0	1/420 (0.2%)	1
Osteomyelitis acute	0/421 (0%)	0	1/420 (0.2%)	1
Peridiverticular abscess	1/421 (0.2%)	1	0/420 (0%)	0
Pneumonia	14/421 (3.3%)	18	12/420 (2.9%)	13
Postoperative wound infection	0/421 (0%)	0	1/420 (0.2%)	1
Sepsis	0/421 (0%)	0	3/420 (0.7%)	3
Septic shock	1/421 (0.2%)	1	0/420 (0%)	0
Urinary tract infection	0/421 (0%)	0	1/420 (0.2%)	1
Injury, poisoning and procedural complications
Accidental overdose	0/421 (0%)	0	1/420 (0.2%)	1
Alcohol poisoning	1/421 (0.2%)	4	0/420 (0%)	0
Ankle fracture	0/421 (0%)	0	1/420 (0.2%)	1
Cervical vertebral fracture	0/421 (0%)	0	1/420 (0.2%)	1
Fibula fracture	1/421 (0.2%)	1	0/420 (0%)	0
Head injury	0/421 (0%)	0	1/420 (0.2%)	1
Incisional hernia	0/421 (0%)	0	1/420 (0.2%)	1
Injury	1/421 (0.2%)	1	0/420 (0%)	0
Open wound	0/421 (0%)	0	1/420 (0.2%)	1
Thermal burn	1/421 (0.2%)	1	0/420 (0%)	0
Tibia fracture	0/421 (0%)	0	1/420 (0.2%)	1
Toxicity to various agents	1/421 (0.2%)	1	0/420 (0%)	0
Investigations
Blood phosphorus decreased	1/421 (0.2%)	1	0/420 (0%)	0
C-reactive protein increased	1/421 (0.2%)	1	0/420 (0%)	0
Metabolism and nutrition disorders
Dehydration	2/421 (0.5%)	2	0/420 (0%)	0
Diabetes mellitus inadequate control	1/421 (0.2%)	2	0/420 (0%)	0
Hypocalcaemia	1/421 (0.2%)	1	0/420 (0%)	0
Hypokalaemia	1/421 (0.2%)	1	0/420 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	2/421 (0.5%)	2	0/420 (0%)	0
Cervical spinal stenosis	1/421 (0.2%)	1	0/420 (0%)	0
Intervertebral disc protrusion	1/421 (0.2%)	1	0/420 (0%)	0
Muscular weakness	0/421 (0%)	0	1/420 (0.2%)	1
Musculoskeletal chest pain	2/421 (0.5%)	2	1/420 (0.2%)	1
Rotator cuff syndrome	0/421 (0%)	0	1/420 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	1/421 (0.2%)	1	0/420 (0%)	0
Brain neoplasm	0/421 (0%)	0	1/420 (0.2%)	1
Breast cancer	1/421 (0.2%)	1	0/420 (0%)	0
Lung neoplasm malignant	1/421 (0.2%)	1	1/420 (0.2%)	1
Metastases to lymph nodes	0/421 (0%)	0	1/420 (0.2%)	1
Oesophageal carcinoma	0/421 (0%)	0	1/420 (0.2%)	1
Squamous cell carcinoma	0/421 (0%)	0	1/420 (0.2%)	1
Throat cancer	0/421 (0%)	0	1/420 (0.2%)	1
Nervous system disorders
Altered state of consciousness	1/421 (0.2%)	1	0/420 (0%)	0
Ataxia	1/421 (0.2%)	1	0/420 (0%)	0
Carotid artery aneurysm	1/421 (0.2%)	1	0/420 (0%)	0
Carotid artery disease	0/421 (0%)	0	1/420 (0.2%)	1
Cerebrovascular accident	1/421 (0.2%)	1	0/420 (0%)	0
Headache	0/421 (0%)	0	1/420 (0.2%)	1
Ischaemic stroke	0/421 (0%)	0	1/420 (0.2%)	1
Sensory disturbance	0/421 (0%)	0	1/420 (0.2%)	1
Syncope	2/421 (0.5%)	2	1/420 (0.2%)	1
Transient ischaemic attack	0/421 (0%)	0	1/420 (0.2%)	1
Psychiatric disorders
Affective disorder	1/421 (0.2%)	4	0/420 (0%)	0
Alcohol withdrawal syndrome	1/421 (0.2%)	1	0/420 (0%)	0
Depression	1/421 (0.2%)	1	1/420 (0.2%)	1
Major depression	0/421 (0%)	0	2/420 (0.5%)	2
Mental status changes	0/421 (0%)	0	1/420 (0.2%)	1
Renal and urinary disorders
Haematuria	1/421 (0.2%)	1	0/420 (0%)	0
Nephropathy	0/421 (0%)	0	1/420 (0.2%)	1
Renal artery stenosis	0/421 (0%)	0	1/420 (0.2%)	1
Renal failure	0/421 (0%)	0	1/420 (0.2%)	1
Renal failure acute	1/421 (0.2%)	1	1/420 (0.2%)	1
Urethral obstruction	1/421 (0.2%)	1	0/420 (0%)	0
Urinary retention	1/421 (0.2%)	1	0/420 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/421 (0%)	0	1/420 (0.2%)	1
Acute respiratory failure	4/421 (1%)	5	1/420 (0.2%)	1
Bronchiectasis	0/421 (0%)	0	1/420 (0.2%)	1
Bronchospasm	1/421 (0.2%)	1	0/420 (0%)	0
Chronic obstructive pulmonary disease	55/421 (13.1%)	76	35/420 (8.3%)	44
Haemoptysis	2/421 (0.5%)	3	0/420 (0%)	0
Hypoxia	0/421 (0%)	0	1/420 (0.2%)	1
Pleuritic pain	1/421 (0.2%)	1	0/420 (0%)	0
Pneumothorax	2/421 (0.5%)	2	0/420 (0%)	0
Pulmonary embolism	1/421 (0.2%)	1	0/420 (0%)	0
Respiratory arrest	0/421 (0%)	0	1/420 (0.2%)	1
Respiratory distress	1/421 (0.2%)	1	0/420 (0%)	0
Respiratory failure	2/421 (0.5%)	3	2/420 (0.5%)	2
Skin and subcutaneous tissue disorders
Urticaria	0/421 (0%)	0	1/420 (0.2%)	1
Vascular disorders
Aortic aneurysm	0/421 (0%)	0	1/420 (0.2%)	1
Hypertension	1/421 (0.2%)	1	0/420 (0%)	0
Hypertensive crisis	0/421 (0%)	0	1/420 (0.2%)	1
Hypertensive emergency	1/421 (0.2%)	1	0/420 (0%)	0
Hypotension	0/421 (0%)	0	1/420 (0.2%)	1
Iliac artery stenosis	0/421 (0%)	0	2/420 (0.5%)	2
Peripheral arterial occlusive disease	0/421 (0%)	0	1/420 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Placebo Comparator: Placebo Twice Daily		Experimental: Arformoterol 15 Mcg Twice Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	180/421 (42.8%)		174/420 (41.4%)
Infections and infestations
Bronchitis	28/421 (6.7%)	36	43/420 (10.2%)	58
Nasopharyngitis	33/421 (7.8%)	49	38/420 (9%)	50
Sinusitis	22/421 (5.2%)	29	19/420 (4.5%)	27
Upper respiratory tract infection	22/421 (5.2%)	26	22/420 (5.2%)	28
Nervous system disorders
Headache	21/421 (5%)	39	35/420 (8.3%)	53
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	83/421 (19.7%)	122	75/420 (17.9%)	115
Dyspnoea	30/421 (7.1%)	46	24/420 (5.7%)	27

Limitations/Caveats

Although LABAs other than study medication were discontinued, other medications were not controlled for. A large number of subjects discontinued after a primary event and their eventual outcomes are unknown.

More Information

Certain Agreements

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

In the event the Study is part of a multi-center study, the first publication of the results of the Study shall be made in conjunction with the results of other participating study sites as a multi-center publication; provided however, if a multi-center publication is not forthcoming within twenty-four (24) months following completion of the Study at all sites, Institution and Investigator shall be free to publish.