Blacks and Exacerbations on Long Acting Beta Agonists (LABA) vs. Tiotropium (BELT)

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01290874
• Collaborator: Olmsted Medical Center (Other), American Academy of Family Physicians National Research Network (Other), Baim Institute for Clinical Research (Other)
• Enrollment: 1,070
• Locations: 13
• Arms: 2
• Duration (Months): 27.1
• Patients Per Site: 82.3
• Patients Per Site Per Month: 3

Study Details

Study Description

Brief Summary

We are doing this study to learn how genes affect the way that people, specifically Black people, respond to treatment for asthma. Recent studies suggest that people respond differently to some asthma medications (eg Serevent, Foradil). Some people feel better when they use these inhalers, but others may not, and some people get worse. It seems that this difference shows up more often in Blacks than in Whites, which is why we are looking for Black subjects for this study. In all people, this difference seems to depend on their genes or DNA. This study is comparing the use of long acting asthma medications (Serevent, Foradil) to Tiotropium (Spiriva) for the treatment of asthma. Spiriva is used to treat chronic obstructive pulmonary disease (COPD). This study will help to see if this medication is also useful for treating asthma and whether it works better for some people than the current asthma medications.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Tiotropium; Drug: Salmeterol; Drug: Formoterol	Phase 3

Detailed Description

Asthma is a chronic respiratory disease that affects over 22 million people in the United States. Asthma produces 500,000 hospital admissions and accounts for 10.1 million days of lost work in adults annually. Asthma has been designated a priority condition of the Effective Health Care Program.

Blacks bear a disproportionate burden of asthma morbidity and mortality. In its 2005 report on ethnic disparities in health care, AHRQ identified hospital admissions for asthma as the second largest disparity in quality of health care for Blacks vs. Caucasians.

Long-acting beta-agonists (LABAs) produce extended increases in airway caliber among patients with asthma via action at the beta2-adrenergic receptor (ADRB2). Adding a LABA to an inhaled corticosteroid controller medication (ICS), can decrease asthma symptoms for many individuals and appears to decrease asthma exacerbations. LABA/ICS has become the most commonly prescribed ICS containing medication.

Drugs acting at ADRB2, including LABAs, have been associated with rare loss of long-term asthma control and increased serious adverse outcomes including death and respiratory failure, even when used with ICS. The risk appears four to five-fold greater in Blacks than non-Black patients with asthma.

Consensus guidelines recommend LABAs be added to ICS in those not completely controlled on ICS alone. These recommendations are based on weighing data on the benefit demonstrated in the general population vs. the rare risk of serious adverse outcomes and balancing the apparent benefits vs. the risks of LABAs (Kramer 2009). However, it appears that LABA/ICS may be significantly less effective in Blacks than Caucasians. Comparison of studies with LABA/ICS in Blacks vs. studies where Blacks were a small minority suggests that Blacks may have much less benefit than other racial groups. Additionally, recent data (Wechsler 2009) suggest that a polymorphism at the 16th position of the ADRB2 gene identifies a group of Blacks (those homozygous for arginine (Arg16Arg)) in whom the response of adding a LABA to an ICS is further diminished. This polymorphism is present in ~20% of US Blacks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1070 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Blacks and Exacerbations on LABA vs. Tiotropium (BELT)
• Study Start Date: Mar 30, 2011
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tiotropium Tiotropium bromide will be evaluated as a treatment for asthma.	Drug: Tiotropium; Tiotropium bromide 18 mcg once daily for one year of treatment.; Other Names: Spiriva
Active Comparator: Salmeterol or Formoterol Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard.	Drug: Salmeterol; Salmeterol 50 mcg twice daily for one year of treatment.; Other Names: Serevent ; Drug: Formoterol; Formoterol 12 mcg twice daily for one year; Other Names: Foradil

Outcome Measures

Primary Outcome Measures

1. Time to Asthma Exacerbation (Mean Number of Exacerbations/Person-year) [evaluated monthly (on average) via questionnaire for 12 months]

   We summarize the survival experience using mean number of exacerbations/person-year and compare it using the log-rank test comparing kaplan-meier survival curve.

Secondary Outcome Measures

1. Change in FEV1 [from baseline to 12 months]

   Average change in lung function (FEV1) evaluated by spirometry per participant over 12 months

2. Change in Asthma Control Questionnaire (ACQ) [from baseline to 12 months]

   Average Change in Asthma Control Score Per Participant Over 12 Months Using the Asthma Control Questionnaire (ACQ). The ACQ has six questions regarding symptoms, rescue short-acting β-agonist use and one about FEV1 % predicted. A 7-point scale (0 = no impairment, 6 = maximum impairment) is used for each question and the ACQ score is the mean value of these questions - hence between 0 (totally controlled) and 6 (severely uncontrolled).

3. Change in Asthma Quality of Life (AQLQ) [from baseline to 12 months]

   Average Change in Asthma Quality of Life Score Per Participant Over 12 Months Using the Asthma Quality of Life Questionnaire (AQLQ). The AQLQ has 32 questions in four domains (symptoms, activity limitation, emotional function, and environmental stimuli) and measures the functional problems that are troublesome to individuals with asthma. Symptoms (11 items), Activity Limitation (12 items, 5 of which are individualized), Emotional Function (5 items), and Environmental Exposure (4 items); 7-point Likert scale (7 = not impaired at all - 1 = severely impaired); scores range 1-7, with higher scores indicating better quality of life.

4. Change in Asthma Symptom Utility Index (ASUI) [from baseline to 12 months]

   Average Change in Asthma Symptom Utility Score Per Participant Over 12 Months Using the Asthma Symptom Utility Index (ASUI). The ASUI is an 11-item preference-based outcome measure used in clinical trials and cost-effectiveness studies for asthma and is designed to assess the frequency and severity of cough, wheeze, dyspnea, nighttime awakenings, and side effects, weighted according to patient preferences. 4-point Likert scale to assess frequency (not at all, 1 to 3 days, 4 to 7 days, and 8 to 14 days) and severity (not applicable, mild, moderate and severe); scores range from 0 (worst possible symptoms) to 1 (no symptoms).

5. Change in Symptom-Free Day Questionnaire (SFDQ) [from baseline to 12 months]

   Average Change in Symptom-Free Days Per Participant Over 12 Months Using the Symptom-Free Day Questionnaire (SFDQ). The asthma symptom free day questionnaire (SFDQ) quantifies the number of days with neither daytime nor nighttime asthma symptoms, nor awakenings due to asthma symptoms.

6. Change in Rescue Medication Use [from baseline to 12 months]

   Average Change in Rescue Medication Use Per Participant Over 12 Months. Monthly questionnaires will evaluate the amount of rescue medication subjects have used on average, measured in puffs per day.

7. Change in Moderate Asthma Deterioration [from baseline to 12 months]

   Average Change in Moderate Asthma Deterioration Per Participant Over 12 Months. The definition of a moderate asthma deterioration should include one or more of the following: deterioration in symptoms, deterioration in lung function, or increased rescue bronchodilator use. These features should last for 2 days or more, but not be severe enough to warrant systemic corticosteroid use and/or hospitalization.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Black (self-identified, with at least one biological parent identified as Black)

2. Male and female subjects, ages 18-75

3. Ability to provide informed consent

4. Clinical history consistent with asthma for > 1 year.

5. Ability to perform pulmonary function tests

6. FEV1 > 40% of predicted

7. Receiving inhaled corticosteroids (ICS)/LABA combination therapy, or ICS moderate dose monotherapy and baseline ACQ>1.25

8. Non-smoker for past year (total lifetime smoking history < 10 pack-years)

Exclusion Criteria:

1. Use of greater than the equivalent of 1000 mcg inhaled fluticasone daily

2. Chronic use of oral corticosteroids or Anti IgE for asthma

3. Lung disease other than asthma or diagnosis of vocal cord dysfunction.

4. Significant medical illness (other than asthma) that is not stable.

5. Pregnancy or lactation or an unwillingness to maintain effective birth control.

6. History of a significant exacerbation of asthma or respiratory tract infection in the prior 4 weeks

7. History of life-threatening asthma requiring treatment with intubation and mechanical ventilation within 5 years.

8. Hypo sensitization therapy other than an established maintenance regimen.

9. Use of inhaled anticholinergic therapy (ipratropium, tiotropium) in prior month

10. Known contraindication to inhaled tiotropium e.g. narrow angle glaucoma, history of bladder neck obstruction or significant symptoms related to prostatic hypertrophy.

11. Inability to speak and read English.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Edward Waters College Medical Center (Mayo)	Jacksonville	Florida	United States	32209
2	Urban Family Practice	Marietta	Georgia	United States	30067
3	Albany Area Primary Healthcare, Inc	Newton	Georgia	United States	39870
4	Northwestern University	Chicago	Illinois	United States	60611
5	Wayne State University	Detroit	Michigan	United States	48201
6	G.A. Carmichael F.H.C.	Canton	Mississippi	United States	39046
7	Swope Parkway Health Center	Kansas City	Missouri	United States	64130
8	Montefiore Medical Group	Bronx	New York	United States	10462
9	UNYNET - Jefferson Family Medicine	Buffalo	New York	United States	14215
10	Carolinas Medical Center - NorthEast (Lovelace)	Kannapolis	North Carolina	United States	28081
11	Cleveland Clinic	Cleveland	Ohio	United States	44195
12	Family Medicine Occupational Health Center	Shaker Heights	Ohio	United States	44120
13	BJHCHS - Hardeeville Medical Center	Ridgeland	South Carolina	United States	29936

Sponsors and Collaborators

• Brigham and Women's Hospital
• Olmsted Medical Center
• American Academy of Family Physicians National Research Network
• Baim Institute for Clinical Research

Investigators

• Principal Investigator: Elliot Israel, MD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Elliot Israel, MD, Director of the Asthma Research Center, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01290874
• Other Study ID Numbers: 2010p001898
• First Posted: Feb 7, 2011
• Last Update Posted: Mar 30, 2018
• Last Verified: Mar 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Elliot Israel, MD, Director of the Asthma Research Center, Brigham and Women's Hospital: Asthma; Blacks; LABA; Tiotropium; Spiriva; African American; Serevent; salmeterol; Foradil; formoterol; Advair; Symbicort; Dulera
• Additional relevant MeSH terms: Asthma; Formoterol Fumarate; Tiotropium Bromide; Salmeterol Xinafoate

Study Results

Participant Flow

Recruitment Details	Initial enrollment began March 30, 2011 at the Asthma Research Center at Brigham and Women's Hospital. Subjects were recruited with print advertisements, internet postings, physician referrals, and by contacting patients in databases who asked to be contacted for studies.
Pre-assignment Detail	Subjects on combination ICS/LABA were switched to equivalent-dose ICS monotherapy at the same time they were assigned to the Tiotropium vs. LABA arm of the study.

Arm/Group Title	Tiotropium	Salmeterol or Formoterol
Arm/Group Description	Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year
Period Title: Overall Study
STARTED	532	538
COMPLETED	122	134
NOT COMPLETED	410	404

Baseline Characteristics

Arm/Group Title	Tiotropium	Salmeterol or Formoterol	Total
Arm/Group Description	Tiotropium bromide will be evaluated as a treatment for asthma. Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year	Total of all reporting groups
Overall Participants	532	538	1070
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.2 (12.6)	45.1 (12.6)	45.15 (12.6)
Sex: Female, Male (Count of Participants)
Female	405 76.1%	408 75.8%	813 76%
Male	127 23.9%	130 24.2%	257 24%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	31 5.8%	36 6.7%	67 6.3%
Not Hispanic or Latino	501 94.2%	502 93.3%	1003 93.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	532 100%	538 100%	1070 100%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Time to Asthma Exacerbation (Mean Number of Exacerbations/Person-year)
Description	We summarize the survival experience using mean number of exacerbations/person-year and compare it using the log-rank test comparing kaplan-meier survival curve.
Time Frame	evaluated monthly (on average) via questionnaire for 12 months

Outcome Measure Data

Analysis Population Description

intention-to-treat

Arm/Group Title	Tiotropium	Salmeterol or Formoterol
Arm/Group Description	Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year
Measure Participants	532	538
Mean (95% Confidence Interval) [event per person-year]	0.37	0.42

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tiotropium, Salmeterol or Formoterol
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Change in FEV1
Description	Average change in lung function (FEV1) evaluated by spirometry per participant over 12 months
Time Frame	from baseline to 12 months

Outcome Measure Data

Analysis Population Description

255 and 253 participants are missing data on change in FEV1 in the Tiotropium and Salmeterol or Formoterol arms, respectively.

Arm/Group Title	Tiotropium	Salmeterol or Formoterol
Arm/Group Description	Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year
Measure Participants	277	285
Mean (95% Confidence Interval) [liters]	-0.018	0.003

3. Secondary Outcome

Title	Change in Asthma Control Questionnaire (ACQ)
Description	Average Change in Asthma Control Score Per Participant Over 12 Months Using the Asthma Control Questionnaire (ACQ). The ACQ has six questions regarding symptoms, rescue short-acting β-agonist use and one about FEV1 % predicted. A 7-point scale (0 = no impairment, 6 = maximum impairment) is used for each question and the ACQ score is the mean value of these questions - hence between 0 (totally controlled) and 6 (severely uncontrolled).
Time Frame	from baseline to 12 months

Outcome Measure Data

Analysis Population Description

334 and 326 participants are missing data on ACQ in the Tiotropium and Salmeterol or Formoterol arms, respectively.

Arm/Group Title	Tiotropium	Salmeterol or Formoterol
Arm/Group Description	Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year
Measure Participants	198	212
Mean (95% Confidence Interval) [units on a scale]	-0.70	-0.66

4. Secondary Outcome

Title	Change in Asthma Quality of Life (AQLQ)
Description	Average Change in Asthma Quality of Life Score Per Participant Over 12 Months Using the Asthma Quality of Life Questionnaire (AQLQ). The AQLQ has 32 questions in four domains (symptoms, activity limitation, emotional function, and environmental stimuli) and measures the functional problems that are troublesome to individuals with asthma. Symptoms (11 items), Activity Limitation (12 items, 5 of which are individualized), Emotional Function (5 items), and Environmental Exposure (4 items); 7-point Likert scale (7 = not impaired at all - 1 = severely impaired); scores range 1-7, with higher scores indicating better quality of life.
Time Frame	from baseline to 12 months

Outcome Measure Data

Analysis Population Description

242 and 239 participants are missing data on AQLQ in the Tiotropium and Salmeterol or Formoterol arms, respectively.

Arm/Group Title	Tiotropium	Salmeterol or Formoterol
Arm/Group Description	Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year
Measure Participants	290	299
Mean (95% Confidence Interval) [units on a scale]	1.00	1.02

5. Secondary Outcome

Title	Change in Asthma Symptom Utility Index (ASUI)
Description	Average Change in Asthma Symptom Utility Score Per Participant Over 12 Months Using the Asthma Symptom Utility Index (ASUI). The ASUI is an 11-item preference-based outcome measure used in clinical trials and cost-effectiveness studies for asthma and is designed to assess the frequency and severity of cough, wheeze, dyspnea, nighttime awakenings, and side effects, weighted according to patient preferences. 4-point Likert scale to assess frequency (not at all, 1 to 3 days, 4 to 7 days, and 8 to 14 days) and severity (not applicable, mild, moderate and severe); scores range from 0 (worst possible symptoms) to 1 (no symptoms).
Time Frame	from baseline to 12 months

Outcome Measure Data

Analysis Population Description

257 and 265 participants are missing data on ASUI in the Tiotropium and Salmeterol or Formoterol arms, respectively.

Arm/Group Title	Tiotropium	Salmeterol or Formoterol
Arm/Group Description	Tiotropium bromide will be evaluated as a treatment for asthma. Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year
Measure Participants	275	273
Mean (95% Confidence Interval) [units on a scale]	0.11	0.10

6. Secondary Outcome

Title	Change in Symptom-Free Day Questionnaire (SFDQ)
Description	Average Change in Symptom-Free Days Per Participant Over 12 Months Using the Symptom-Free Day Questionnaire (SFDQ). The asthma symptom free day questionnaire (SFDQ) quantifies the number of days with neither daytime nor nighttime asthma symptoms, nor awakenings due to asthma symptoms.
Time Frame	from baseline to 12 months

Outcome Measure Data

Analysis Population Description

The instrument used to collect data proved to be unreliable. The statistic for internal consistency demonstrated less than 30% internal consistency.

Arm/Group Title	Tiotropium	Salmeterol or Formoterol
Arm/Group Description	Tiotropium bromide will be evaluated as a treatment for asthma. Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year
Measure Participants	0	0

7. Secondary Outcome

Title	Change in Rescue Medication Use
Description	Average Change in Rescue Medication Use Per Participant Over 12 Months. Monthly questionnaires will evaluate the amount of rescue medication subjects have used on average, measured in puffs per day.
Time Frame	from baseline to 12 months

Outcome Measure Data

Analysis Population Description

335 and 328 participants are missing data on rescue medication use in the Tiotropium and Salmeterol or Formoterol arms, respectively.

Arm/Group Title	Tiotropium	Salmeterol or Formoterol
Arm/Group Description	Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year
Measure Participants	197	210
Mean (95% Confidence Interval) [units on a scale]	-0.92	-0.97

8. Secondary Outcome

Title	Change in Moderate Asthma Deterioration
Description	Average Change in Moderate Asthma Deterioration Per Participant Over 12 Months. The definition of a moderate asthma deterioration should include one or more of the following: deterioration in symptoms, deterioration in lung function, or increased rescue bronchodilator use. These features should last for 2 days or more, but not be severe enough to warrant systemic corticosteroid use and/or hospitalization.
Time Frame	from baseline to 12 months

Outcome Measure Data

Analysis Population Description

Inadequate baseline data was collected so that the change in this variable could not be assessed.

Arm/Group Title	Tiotropium	Salmeterol or Formoterol
Arm/Group Description	Tiotropium bromide will be evaluated as a treatment for asthma. Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.	Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year
Measure Participants	0	0

Adverse Events

Time Frame	Adverse events were reported from the time of patient enrollment to up to 18 months after study completion.
Arm/Group Title	Tiotropium		Salmeterol or Formoterol
Arm/Group Description	Tiotropium: Tiotropium bromide 18 mcg once daily for one year of treatment.		Long acting beta agonists (Serevent, Foradil) are the standard treatments for moderate asthma. The efficacy of Tiotropium will be compared to this standard. Salmeterol: Salmeterol 50 mcg twice daily for one year of treatment. Formoterol: Formoterol 12 mcg twice daily for one year
All Cause Mortality
	Tiotropium		Salmeterol or Formoterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tiotropium		Salmeterol or Formoterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	84/532 (15.8%)		69/538 (12.8%)
Cardiac disorders
Acute Myocardial Infarction	2/532 (0.4%)	2	1/538 (0.2%)	1
Angina Pectoris	1/532 (0.2%)	1	0/538 (0%)	0
Angina Unstable	1/532 (0.2%)	1	1/538 (0.2%)	1
Cardiac Disorder	0/532 (0%)	0	1/538 (0.2%)	1
Cardiac Failure Congestive	3/532 (0.6%)	3	2/538 (0.4%)	2
Cardiomyopathy	1/532 (0.2%)	1	0/538 (0%)	0
Cardiopulmonary Failure	1/532 (0.2%)	1	0/538 (0%)	0
Coronary Artery Disease	1/532 (0.2%)	1	1/538 (0.2%)	1
Coronary Artery Occlusion	1/532 (0.2%)	1	0/538 (0%)	0
Dysponea	0/532 (0%)	0	1/538 (0.2%)	1
Myocardial Infarction	1/532 (0.2%)	1	1/538 (0.2%)	1
Tachycardia	0/532 (0%)	0	2/538 (0.4%)	2
Endocrine disorders
Goitre	1/532 (0.2%)	1	0/538 (0%)	0
Eye disorders
Vision blurred	0/532 (0%)	0	1/538 (0.2%)	1
Gastrointestinal disorders
Abdominal Distension	0/532 (0%)	0	1/538 (0.2%)	1
Abdominal Hernia	1/532 (0.2%)	1	0/538 (0%)	0
Abdominal Pain	1/532 (0.2%)	1	0/538 (0%)	0
Diarrhoea	0/532 (0%)	0	1/538 (0.2%)	1
Diverticulum Intestinal	1/532 (0.2%)	1	0/538 (0%)	0
Gastritis	0/532 (0%)	0	1/538 (0.2%)	1
Hiatus Hernia	1/532 (0.2%)	1	0/538 (0%)	0
Impaired Gastric Emptying	0/532 (0%)	0	1/538 (0.2%)	1
Rectal Haemorrhage	0/532 (0%)	0	1/538 (0.2%)	1
Small Intestinal Obstruction	0/532 (0%)	0	1/538 (0.2%)	1
Upper Gastrointestinal Haemorrhage	1/532 (0.2%)	1	0/538 (0%)	0
General disorders
Chest Discomfort	1/532 (0.2%)	1	1/538 (0.2%)	1
Chest Pain	8/532 (1.5%)	8	6/538 (1.1%)	6
Non-cardiac chest pain	2/532 (0.4%)	2	2/538 (0.4%)	2
Oedema	1/532 (0.2%)	1	0/538 (0%)	0
Oedema Peripheral	0/532 (0%)	0	1/538 (0.2%)	1
Disease Progression	1/532 (0.2%)	1	0/538 (0%)	0
Hepatobiliary disorders
Gallbladder Disorder	0/532 (0%)	0	1/538 (0.2%)	1
Immune system disorders
Anaphylactic Reaction	0/532 (0%)	0	1/538 (0.2%)	1
Infections and infestations
Appendicitis	1/532 (0.2%)	1	0/538 (0%)	0
Diverticulitis	0/532 (0%)	0	1/538 (0.2%)	1
Gastrointestinal bacterial infection	1/532 (0.2%)	1	0/538 (0%)	0
Localized Infection	0/532 (0%)	0	1/538 (0.2%)	1
Pyelonephritis	0/532 (0%)	0	1/538 (0.2%)	1
Sepsis	1/532 (0.2%)	1	1/538 (0.2%)	1
Urinary tract infection	1/532 (0.2%)	1	0/538 (0%)	0
Viral infection	1/532 (0.2%)	1	0/538 (0%)	0
Wound infection	1/532 (0.2%)	1	0/538 (0%)	0
Injury, poisoning and procedural complications
Incisional hernia	1/532 (0.2%)	1	0/538 (0%)	0
Investigations
Blood glucose increased	1/532 (0.2%)	1	0/538 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/532 (0%)	0	1/538 (0.2%)	1
Diabetes mellitus	1/532 (0.2%)	1	0/538 (0%)	0
Diabetic ketoacidosis	0/532 (0%)	0	1/538 (0.2%)	1
Hyperglycaemia	0/532 (0%)	0	1/538 (0.2%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/532 (0%)	0	1/538 (0.2%)	1
Arthritis	0/532 (0%)	0	1/538 (0.2%)	1
Back pain	0/532 (0%)	0	2/538 (0.4%)	2
Costochondritis	1/532 (0.2%)	1	0/538 (0%)	0
Intervertebral disc protrusion	0/532 (0%)	0	1/538 (0.2%)	1
Osteoarthritis	1/532 (0.2%)	1	0/538 (0%)	0
Pain in extremity	1/532 (0.2%)	1	0/538 (0%)	0
Rheumatoid arthritis	1/532 (0.2%)	1	0/538 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm	1/532 (0.2%)	1	0/538 (0%)	0
Breast cancer	1/532 (0.2%)	1	0/538 (0%)	0
Endometrial cancer	0/532 (0%)	0	1/538 (0.2%)	1
Uterine leiomyoma	0/532 (0%)	0	1/538 (0.2%)	1
Nervous system disorders
Cerebral cyst	1/532 (0.2%)	1	0/538 (0%)	0
Cerebrovascular accident	0/532 (0%)	0	1/538 (0.2%)	1
Convulsion	0/532 (0%)	0	2/538 (0.4%)	2
Dizziness	0/532 (0%)	0	1/538 (0.2%)	1
Dysarthria	0/532 (0%)	0	1/538 (0.2%)	1
Headache	1/532 (0.2%)	1	0/538 (0%)	0
Hemiparesis	0/532 (0%)	0	1/538 (0.2%)	1
Hypoaesthesia	0/532 (0%)	0	1/538 (0.2%)	1
Loss of consciousness	1/532 (0.2%)	1	0/538 (0%)	0
Myelopathy	1/532 (0.2%)	1	0/538 (0%)	0
Syncope	0/532 (0%)	0	1/538 (0.2%)	1
Transient ischaemic attack	0/532 (0%)	0	1/538 (0.2%)	1
Psychiatric disorders
Depression	2/532 (0.4%)	2	0/538 (0%)	0
Mental status change	1/532 (0.2%)	1	0/538 (0%)	0
Renal and urinary disorders
Nephrolithiasis	1/532 (0.2%)	1	1/538 (0.2%)	1
Renal failure	0/532 (0%)	0	1/538 (0.2%)	1
Renal failure acute	2/532 (0.4%)	2	0/538 (0%)	0
Reproductive system and breast disorders
Menorrhagia	0/532 (0%)	0	1/538 (0.2%)	1
Postmenopausal haemorrhage	0/532 (0%)	0	1/538 (0.2%)	1
Vaginal haemorrhage	0/532 (0%)	0	1/538 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Bronchitis	2/532 (0.4%)	2	0/538 (0%)	0
Pneumonia	7/532 (1.3%)	7	5/538 (0.9%)	5
Dyspnoea	1/532 (0.2%)	1	1/538 (0.2%)	1
Hypoxia	1/532 (0.2%)	1	0/538 (0%)	0
Pulmonary embolism	1/532 (0.2%)	1	1/538 (0.2%)	1
Asthma	30/532 (5.6%)	30	23/538 (4.3%)	23
Skin and subcutaneous tissue disorders
Angioedema	0/532 (0%)	0	1/538 (0.2%)	1
Blister	0/532 (0%)	0	1/538 (0.2%)	1
Vascular disorders
Deep vein thrombosis	1/532 (0.2%)	1	0/538 (0%)	0
Hypertension	1/532 (0.2%)	1	0/538 (0%)	0
Hypertensive crisis	2/532 (0.4%)	2	0/538 (0%)	0
Hypotension	0/532 (0%)	0	2/538 (0.4%)	2
Peripheral arterial occlusive disease	0/532 (0%)	0	1/538 (0.2%)	1
Vasculitis	0/532 (0%)	0	1/538 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Tiotropium		Salmeterol or Formoterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	338/532 (63.5%)		342/538 (63.6%)
General disorders
Disease Progression	211/532 (39.7%)	211	203/538 (37.7%)	203
Respiratory, thoracic and mediastinal disorders
Asthma	127/532 (23.9%)	127	139/538 (25.8%)	139

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.