Validation of a New Shortness of Breath With Daily Activities Questionnaire in Patients With Chronic Obstructive Pulmonary Disease

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00984659
• Collaborator: (none)
• Enrollment: 366
• Locations: 39
• Arms: 3
• Duration (Months): 8
• Patients Per Site: 9.4
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate a new questionnaire to capture the patient experience of COPD. The information collected will be used to validate the Shortness of Breath with Daily Activities Questionnaire.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Fluticasone propionate/salmeterol combination product; Drug: Salmeterol; Drug: Placebo	Phase 4

Detailed Description

Dyspnea, referred to by patients as "shortness of breath" or "breathlessness," is frequently associated with decreases in functional status, quality of life, and disabilities. Currently available questionnaires do not specifically address the shortness of breath component of COPD. The development of a patient reported outcome questionnaire that will specifically assess Shortness of Breath with Daily Activities (SOBDA) in patients with COPD is needed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 366 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: Validation of a New Shortness of Breath With Daily Activities Questionnaire in Patients With Chronic Obstructive Pulmonary Disease
• Study Start Date: Oct 29, 2009
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FSC Fluticasone propionate/salmeterol combination product 250/50mcg DISKUS twice a day	Drug: Fluticasone propionate/salmeterol combination product; Fluticasone propionate/salmeterol combination product 250/50mcg DISKUS twice a day for 8 weeks
Experimental: SAL Salmeterol 50mcg DISKUS twice a day	Drug: Salmeterol; Salmeterol 50mcg DISKUS twice a day for 8 weeks
Placebo Comparator: Placebo Placebo DISKUS twice a day	Drug: Placebo; Placebo DISKUS twice a day for 8 weeks

Outcome Measures

Primary Outcome Measures

1. Internal Consistency (IC) of the Shortness of Breath With Daily Activities (SOBDA) Questionnaire in Participants With Chronic Obstructive Pulmonary Disease (COPD) Assessed as Cronbach's Alpha Value [Day 1 of the 2-week Run-in Period]

   Cronbach's alpha (CA) is a measure of the IC of the 13-item SOBDA questionnaire (completed via electronic diary by a sample of participants). It is the ratio of the variance (var.) of the sum of the individual scores and the var. of the total score. The var. of the sum of a group of independent variables is the sum of their var.; thus, if the variables are positively correlated, the var. of the sum will be increased. If the items making up the score are identical and so perfectly correlated, CA=1. If the items are independent, CA=0. Higher scores indicate a more reliable (precise) instrument.

2. Test-retest Reliability (T-RR) of SOBDA Scores Measured as the Difference in the SOBDA Weekly Score Between Week 1 and Week 2 of the 2-week Run-in Period [Week 1 and Week 2 of the 2-week Run-in Period]

   T-RR=stability during repeat measures over time in a stable population. SOBDA score was determined by the 13-item (it.) scoring algorithm, assigning a weekly mean score of 1-4 (higher scores=more severe breathlessness with daily activities) based on the mean of 7 days of data (or >=4 days). Daily total score is computed from the mean of the participant's (par.) scores on the 13 it. (>=7 it. must have non-missing responses). Only scores of stable par. (indicating no change [score=3] on the par.-completed Patient Global Assessment of Change [PGAC]; 1 [ much worse] to 5 [much better]) were used.

3. Convergent Validity for the SOBDA Questionnaire Measured as Correlations of the Baseline SOBDA Score With Participant-completed Modified Medical Research Council (mMRC) and Physician-completed mMRC Scores at Visit 2 [Baseline (last week of the 2-week Run-in Period) and pre-treatment on Visit 2 (Day 1 of the 6-week Treatment Period)]

   Convergent validity is defined as the ability of the SOBDA questionnaire to measure required information and was assessed by examining the relationship between the SOBDA score and the participant/physician-completed mMRC Dyspnea Scale assessments. The physician/participant rated the degree of the participant's dyspnea (trouble breathing) on the 5-point mMRC scale (0, none; 4, very severe). Spearman's rank correlation coefficient assesses if the relationship between two variables is monotone. A correlation of +1 or -1 will occur if one variable is a perfect monotone of the other.

4. Convergent Validity for the SOBDA Questionnaire Measured as the Correlation of the Baseline SOBDA Score With the Clinician Global Assessment of Dyspnea Severity (CGI-S) Score at Visit 2 [Baseline (last week of the 2-week Run-in Period) and pre-treatment on Visit 2 (Day 1 of the 6-week Treatment Period)]

   Convergent validity is defined as the ability of the SOBDA questionnaire to measure the required information and was assessed by examining the relationship between the SOBDA score with the CGI-S score. Spearman's rank correlation coefficient assesses if the relationship between two variables is monotone. A correlation of +1 or -1 will occur if one variable is a perfect monotone of the other. Clinicians were asked to assess the severity of the participant's dyspnea on the CGI-S scale. This was evaluated on a 1-4 Likert scale: 1 (mild) to 4 (very severe).

5. Convergent Validity (CV) for the SOBDA Questionnaire Measured as the Correlation of the Baseline SOBDA Score With the Chronic Respiratory Disease Questionnaire-Self-Administered Standardized (CRQ-SAS) Dyspnea Domain Score at Visit 2 [Baseline (last week of the 2-week Run-in Period) and pre-treatment on Visit 2 (Day 1 of the 6-week Treatment Period)]

   Convergent validity is defined as the ability of the SOBDA questionnaire to measure required information and was assessed by examining the relationship between the SOBDA score and the CRQ-SAS dyspnea domain score. Pearson's correlation coefficient is a measure of the linear dependence between 2 variables. A correlation of +1 or -1 will occur if the data from the 2 variables lie exactly on a line. The CRQ is a 20-item instrument measuring 4 domains (each measured on a scale of 1 [maximum impairment] to 7 [no impairment]) of functioning: mastery, fatigue, emotional function, and dyspnea.

6. Known Group Validity for the SOBDA Questionnaire Measured as the Comparison of the Baseline SOBDA Score in the Indicated Categories of the Physician-completed (PyC) mMRC Score at Visit 2 [Baseline (last week of the 2-week Run-in Period) and pre-treatment on Visit 2 (Day 1 of the 6-week Treatment Period)]

   SOBDA known group validity refers to the extent to which scores from the SOBDA questionnaire should differentiate participants with varying levels of dyspnea severity. It was assessed by comparing summary measures for the SOBDA score for each indicated level (0, 1, 2, 3, and 4) of the PyC mMRC. The physician rated the degree of the participant's dyspnea on the 5-point mMRC scale: 0 (none) to 4 (very severe). Known group validity was confirmed if the SOBDA score increased with increasing values of PyC mMRC, both indicating increased levels of breathlessness.

7. Known Group Validity for the SOBDA Questionnaire Measured as the Comparison of the Baseline SOBDA Score in the Indicated Categories of the Participant-completed (ParC) mMRC Score at Visit 2 [Baseline (last week of the 2-week Run-in Period) and pre-treatment on Visit 2 (Day 1 of the 6-week Treatment Period)]

   SOBDA known group validity refers to the extent to which scores from the SOBDA questionnaire should differentiate participants with varying levels of dyspnea severity. It was assessed by comparing summary measures for the SOBDA score for each indicated level (0, 1, 2, 3, and 4) of the ParC mMRC. The participant rated the degree of his/her dyspnea on the 5-point mMRC scale: 0 (none) to 4 (very severe). Known group validity was confirmed if the SOBDA score increased with increasing values of ParC mMRC, both indicating increased levels of breathlessness.

8. Known Group Validity (KGV) for the SOBDA Questionnaire Measured as the Comparison of the Baseline SOBDA Score in the Indicated Categories of CGI-S Scores at Visit 2 [Baseline (last week of the 2-week Run-in Period) and pre-treatement on Visit 2 (Day 1 of the 6-week Treatment Period)]

   SOBDA KGV refers to the extent to which scores from the SOBDA questionnaire should differentiate participants with varying levels of dyspnea severity. It was assessed by comparing summary measures for the SOBDA score for each indicated level (0, 1, 2, 3, and 4) of the CGI-S score. Clinicians were asked to assess the severity of the participant's dyspnea on the CGI-S scale. This was evaluated on a 1-4 Likert scale: 1 (mild) to 4 (very severe). KGV was confirmed if the SOBDA score increased with increasing values of CGI-S, both indicating increased levels of breathlessness.

9. Participants (Par.) Classified as Responders/Non-responders According to the Patient Global Assessment of Change (PGAC) Response at Days 8, 15, 22, 29, 36, and 43 and at Visit 3/Premature Discontinuation (PD) (the End of the 6-week Treatment Period or PD) [Days 8, 15, 22, 29, 36, and 43 and Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

   The PGAC is par. completed on a 1-5 scale: 1, much worse; 2, worse; 3, no change; 4, better; 5, much better. Responders were defined as par. with a rating of "better" or "much better" (score of 4 or 5) on the PGAC at the relevant week; non-responders were defined as par. with a response of "much worse," "worse," or "no change" on the PGAC. As pre-specified in the study protocol, results are presented independent of treatment allocation . The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

10. Change From the Previous Week to the Current Week's SOBDA Score by Participant-completed PGAC Response at Days 8, 15, 22, 29, 36, and 43 and at Visit 3/PD (End of the 6-week Treatment Period or PD) [Baseline; Days 8, 15, 22, 29, 36, and 43 and Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

    Responsiveness reflects the ability of the SOBDA questionnaire to detect change under conditions of known change. Responders (Rs)=participants (par.) with a rating of "better"/"much better" (score of 4/5) on the PGAC (range; 1 [much worse] to 5 [much better]) at the relevant week; NRs=par. with a response of "much worse," "worse," or "no change" (score of 3). Mean difference between Rs and NRs in the change from the previous week to the current week's SOBDA score was calculated. For Visit 3/PD, the change from Baseline to the last treatment week's SOBDA score for Rs and NRs was calculated.

11. Number of Participants Classified as Responders and Non-responders by Clinician Global Impression of Change Question (CGI-C) Response at Visit 3/PD [Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

    Clinicians were asked to provide their clinical impression regarding change in the participant's shortness of breath by CGI-C. This was evaluated on a 1-5 Likert scale: 1 (much worse) to 5 (much better), with 3 being no change. A CGI-C responder was defined as a participant who had a response of "better" (4) or "much better" (5), and a non-responder was defined as a participant who had a response of "much worse" (1), "worse" (2), or "no change" (3).

12. Number of Participants Classified as Responders and Non-responders by CRQ-SAS Dyspnea Domain Response at Visit 3/PD [Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

    A CRQ-SAS dyspnea domain responder was defined as a participant who had a score increase of 0.5 units or more for the dyspnea domain of the CRQ-SAS between Visit 2 and Visit 3/Premature Discontinuation. A non-responder was defined as a participant who had a decrease in the score, or an increase of less than 0.5 units.

13. Number of Participants Classified as Responders and Non-responders by Physician-completed and Participant-completed mMRC Response at Visit 3/PD [Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

    A Physician-completed and Participant-completed mMRC responder was defined as a participant who had a score decrease of one unit or more between Visit 2 and Visit 3/Premature Discontinuation. A non-responder was defined as a participant who had the same score or an increase in score.

14. Change From Baseline to Last Treatment Week in the SOBDA Score by CGI-C Responses at Visit 3/PD [Baseline (2-week Run-in Period) and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

    The responsiveness of the SOBDA questionnaire was assessed by comparing score changes between responders and non-responders. The CGI-C is clinician completed on a 1 to 5 scale: 1, much worse; 2, worse; 3, no change; 4, better; 5, much better. Changes in mean SOBDA scores during the last week of treatment in responders and non-responders using definitions based on the CGI-C conducted at Visit 3/Premature Discontinuation were assessed.

15. Change From Baseline to Last Treatment Week in the SOBDA Score by CRQ-SAS Dyspnea Domain (DD) Responses at Visit 3/PD [Baseline (2-week Run-in Period) and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

    The responsiveness of the SOBDA questionnaire was assessed by comparing score changes of responders (Rs) versus non-responders (NRs). The CRQ-SAS DD includes 5 questions (q.) scored 1 (maximum impairment) to 7 (no impairment). Individual q. were equally weighted, and domain scores (DSs) (range=1-7) were calculated as the mean across the non-missing items within each domain (DSs were calculated although an individual item score was missing). Changes in mean SOBDA scores during the last treatment week in Rs and NRs using definitions based on the CRQ-SAS DD conducted at Visit 3/PD were assessed.

16. Change From Baseline to Last Treatment Week in the SOBDA Score by Physician-completed mMRC and Participant-completed mMRC Responses at Visit 3/PD [Baseline (2-week Run-in Period) and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

    The responsiveness of the SOBDA questionnaire was assessed by comparing score changes between responders and non-responders. The mMRC ranges from 0 (no breathlessness except with strenous exercise) to 4 (too breathless to leave the house; breathless when dressing/undressing) and is completed by the clinician or the participant as indicated. Changes in mean SOBDA scores during the last week of treatment in responders and non-responders using definitions based on the Physician-completed (Ph-C) and Participant-completed (Pa-C) mMRC conducted at Visit 3/Premature Discontinuation were assessed.

17. SOBDA Threshold for Response Assessed as Mean Change From the Previous Week's SOBDA Score Based on a Participant-completed PGAC Score Rated of "Better" [Baseline (last week of the 2-week Run-in Period) and Weeks 1, 2, 3, 4, 5, and 6 (6-week Treatment Period)]

    Changes from Baseline in the SOBDA score for responders (Rs) and non-responders (NRs) (using the PGAC assessment; 1 [much worse] to 5 [much better]), together with the cumulative proportions of Rs and NRs, was used to establish the threshold for defining SOBDA questionnaire Rs. The threshold of response is a score change in the SOBDA questionnaire that is demonstrated to have a perceivable benefit for the participant. The threshold of response was evaluated as the change from Baseline in the SOBDA score based on PGAC scores pre-specified as "better" or demonstrating meaningful improvement.

18. SOBDA Threshold for Response as Assessed by Mean Change From Baseline to the Last Treatment Week in the SOBDA Score Based on a CGI-C Response Rated as "Better" [Baseline and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

    The threshold of response is a score change in the SOBDA questionnaire that is demonstrated to have a perceivable benefit for the participant. The threshold of response was evaluated as the change from Baseline in the SOBDA score based on CGI-C scores pre-specified as "better" or demonstrating meaningful improvement. The CGI-C is clinician completed on a 1 to 5 scale: 1, much worse, 2, worse; 3, no change; 4, better; 5, much better.

19. SOBDA Threshold for Response as Assessed by Mean Change From Baseline to the Last Treatment Week in the SOBDA Score Based on a CRQ-SAS Dyspnea Domain (DD) Response Rated as "Better" [Baseline and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

    The threshold of response (TOR) is a score change in the SOBDA questionnaire that is demonstrated to have a perceivable benefit. The TOR was evaluated as the change from Baseline in the SOBDA score based on CRQ-SAS scores pre-specified as "better" or demonstrating meaningful improvement. The CRQ-SAS DD includes 5 questions (q.) scored 1 (maximum impairment) to 7 (no impairment). Individual q. were equally weighted, and domain scores (DSs) (range=1-7) were calculated as the mean across the non-missing items within each domain (DSs were calculated although an individual item score was missing).

20. SOBDA Threshold for Response Assessed as Mean Change From Baseline to Last Treatment Week in the SOBDA Score Based on Forced Expiratory Volume in One Second (FEV1) Change From Baseline of 50 Milliliters (mL) to <100 mL [Baseline and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)]

    FEV1 response was rated as 1=No change or worse (i.e., change of <50 mL); 2=Better (i.e., change of 50 to <100 mL); 3=Much better (i.e., change of >=100 mL). The threshold of response is a score change in the SOBDA questionnaire that is demonstrated to have a perceivable benefit for the participant. The threshold of response was evaluated as the change from Baseline in the SOBDA score based on study assessment (FEV1) scores pre-specified as "better" or demonstrating meaningful improvement.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adults ≥ 40 years of age

• Established clinical history of COPD by ATS/ERS definition

• Former or current smoker > 10 pack years

• Evidence of dyspnea

Exclusion Criteria:

• Has a respiratory disorder other than COPD

• Cancer not in complete clinical remission

• Clinically significant cardiovascular, neurological, psychiatric, renal, gastro-intestinal, immunological, endocrine, or hematological abnormalities that are uncontrolled

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Jasper	Alabama	United States	35501
2	GSK Investigational Site	Mobile	Alabama	United States	36608
3	GSK Investigational Site	Los Angeles	California	United States	90095-1690
4	GSK Investigational Site	Riverside	California	United States	92506
5	GSK Investigational Site	Wheat Ridge	Colorado	United States	80033
6	GSK Investigational Site	Stamford	Connecticut	United States	06902
7	GSK Investigational Site	Tamarac	Florida	United States	33321
8	GSK Investigational Site	Decatur	Georgia	United States	30033
9	GSK Investigational Site	Lawrenceville	Georgia	United States	30046
10	GSK Investigational Site	Evansville	Indiana	United States	47710
11	GSK Investigational Site	Evansville	Indiana	United States	47714
12	GSK Investigational Site	South Bend	Indiana	United States	46617
13	GSK Investigational Site	Madisonville	Kentucky	United States	42431
14	GSK Investigational Site	New Orleans	Louisiana	United States	70115
15	GSK Investigational Site	Sunset	Louisiana	United States	70584
16	GSK Investigational Site	Saint Louis	Missouri	United States	63141
17	GSK Investigational Site	Summit	New Jersey	United States	07091
18	GSK Investigational Site	Charlotte	North Carolina	United States	28207
19	GSK Investigational Site	Elizabeth City	North Carolina	United States	27909
20	GSK Investigational Site	Canton	Ohio	United States	44718
21	GSK Investigational Site	Cincinnati	Ohio	United States	45231
22	GSK Investigational Site	Lake Oswego	Oregon	United States	97035
23	GSK Investigational Site	Portland	Oregon	United States	97213
24	GSK Investigational Site	Erie	Pennsylvania	United States	16508
25	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19140
26	GSK Investigational Site	Charleston	South Carolina	United States	29406-7108
27	GSK Investigational Site	Chester	South Carolina	United States	29706
28	GSK Investigational Site	Clinton	South Carolina	United States	29325
29	GSK Investigational Site	Easley	South Carolina	United States	29640
30	GSK Investigational Site	Gaffney	South Carolina	United States	29340
31	GSK Investigational Site	Greenwood	South Carolina	United States	29646
32	GSK Investigational Site	Seneca	South Carolina	United States	29678
33	GSK Investigational Site	Spartanburg	South Carolina	United States	29303
34	GSK Investigational Site	Johnson City	Tennessee	United States	37601
35	GSK Investigational Site	Houston	Texas	United States	77054
36	GSK Investigational Site	New Braunfels	Texas	United States	78130
37	GSK Investigational Site	Abingdon	Virginia	United States	24210
38	GSK Investigational Site	Richmond	Virginia	United States	23229
39	GSK Investigational Site	Spokane	Washington	United States	99204

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00984659
• Other Study ID Numbers: 112989
• First Posted: Sep 25, 2009
• Last Update Posted: Aug 29, 2018
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: Pulmonary Disease, Chronic Obstructive; Dyspnea
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Dyspnea; Chronic Disease; Fluticasone; Xhance; Salmeterol Xinafoate

Study Results

Participant Flow

Recruitment Details	The number of participants "enrolled" in the Protocol reflects the number of participants starting treatment in the Double-blind Treatment Period.
Pre-assignment Detail	After Screening (Visit 1), the study commenced with a 2-week Run-in Period, during which participants were permitted to use albuterol and/or ipratropium as rescue medication. Eligible participants at Visit 2 were randomized to receive one of three treatments in the 6-week Double-blind Treatment Period.

Arm/Group Title	Albuterol and/or Ipratropium: Run-in Period	Placebo: Double-blind Treatment Period	SAL 50 mcg: Double-blind Treatment Period	FSC 250/50 mcg: Double-blind Treatment Period
Arm/Group Description	Participants were permitted to use albuterol and/or ipratropium as rescue medication during the 2-week Run-in Period	Matching placebo via DISKUS, administered as one inhalation twice daily (BID) during the 6-week Double-blind Treatment Period	Salmeterol xinafoate (SAL) 50 micrograms (mcg) per inhalation via DISKUS, administered as one inhalation BID during the 6-week Double-blind Treatment Period	Fluticasone propionate and salmeterol xinafoate fixed dose combination product (FSC) 250/50 mcg per inhalation via DISKUS, administered as one inhalation BID during the 6-week Double-blind Treatment Period
Period Title: 2-week Run-in Period
STARTED	418	0	0	0
COMPLETED	366	0	0	0
NOT COMPLETED	52	0	0	0
Period Title: 2-week Run-in Period
STARTED	0	75	152	139
COMPLETED	0	69	141	126
NOT COMPLETED	0	6	11	13

Baseline Characteristics

Arm/Group Title	Placebo	SAL 50 mcg	FSC 250/50 mcg	Albuterol and/or Ipratropium: Run-in Failure	Total
Arm/Group Description	Matching placebo via DISKUS, administered as one inhalation twice daily (BID)	Salmeterol xinafoate (SAL) 50 micrograms (mcg) per inhalation via DISKUS, administered as one inhalation BID	Fluticasone propionate and salmeterol xinafoate fixed dose combination product (FSC) 250/50 mcg per inhalation via DISKUS, administered as one inhalation BID	Participants who entered the 2-week Run-in Period, during which they were permitted to use albuterol and/or ipratropium as rescue medication, but then failed to be randomized, or were randomized but did not receive a dose of study medication	Total of all reporting groups
Overall Participants	75	152	139	52	418
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.8 (9.82)	60.1 (9.58)	60.2 (9.45)	63.8 (9.61)	61.1 (9.65)
Sex: Female, Male (Count of Participants)
Female	29 38.7%	63 41.4%	60 43.2%	27 51.9%	179 42.8%
Male	46 61.3%	89 58.6%	79 56.8%	25 48.1%	239 57.2%
Race/Ethnicity, Customized (participants) [Number]
African American/African Heritage	9 12%	12 7.9%	12 8.6%	8 15.4%	41 9.8%
Asian	1 1.3%	0 0%	0 0%	0 0%	1 0.2%
White	65 86.7%	140 92.1%	127 91.4%	44 84.6%	376 90%

Outcome Measures

1. Primary Outcome

Title	Internal Consistency (IC) of the Shortness of Breath With Daily Activities (SOBDA) Questionnaire in Participants With Chronic Obstructive Pulmonary Disease (COPD) Assessed as Cronbach's Alpha Value
Description	Cronbach's alpha (CA) is a measure of the IC of the 13-item SOBDA questionnaire (completed via electronic diary by a sample of participants). It is the ratio of the variance (var.) of the sum of the individual scores and the var. of the total score. The var. of the sum of a group of independent variables is the sum of their var.; thus, if the variables are positively correlated, the var. of the sum will be increased. If the items making up the score are identical and so perfectly correlated, CA=1. If the items are independent, CA=0. Higher scores indicate a more reliable (precise) instrument.
Time Frame	Day 1 of the 2-week Run-in Period

Outcome Measure Data

Analysis Population Description

Run-in Population: all participants who completed Visit 2 (Day 1 of Treatment Period), including those who were not randomized, were randomized but did not receive a dose of study medication, and those who were randomized and received study medication. Participants with a score for each SOBDA item on Day 1 of the 2-week Run-in Period were analyzed.

Arm/Group Title	All Participants: 2-week Run-in Period
Arm/Group Description	All participants in the 2-week Run-in Period. Participants were permitted to use albuterol and/or ipratropium as rescue medication during this period.
Measure Participants	344
Number [ratio of variance]	0.892

2. Primary Outcome

Title	Test-retest Reliability (T-RR) of SOBDA Scores Measured as the Difference in the SOBDA Weekly Score Between Week 1 and Week 2 of the 2-week Run-in Period
Description	T-RR=stability during repeat measures over time in a stable population. SOBDA score was determined by the 13-item (it.) scoring algorithm, assigning a weekly mean score of 1-4 (higher scores=more severe breathlessness with daily activities) based on the mean of 7 days of data (or >=4 days). Daily total score is computed from the mean of the participant's (par.) scores on the 13 it. (>=7 it. must have non-missing responses). Only scores of stable par. (indicating no change [score=3] on the par.-completed Patient Global Assessment of Change [PGAC]; 1 [ much worse] to 5 [much better]) were used.
Time Frame	Week 1 and Week 2 of the 2-week Run-in Period

Outcome Measure Data

Analysis Population Description

Run-in Population. Data from participants with weekly SOBDA scores at Week 1 and Week 2 of the 2-week Run-in Period and reporting no change on the second weekly PGAC were analyzed.

Arm/Group Title	All Participants: 2-week Run-in Period
Arm/Group Description	All participants in the 2-week Run-in Period. Participants were permitted to use albuterol and/or ipratropium as rescue medication during this period.
Measure Participants	152
Mean (Standard Deviation) [scores on a scale]	0.01 (0.244)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.713
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Convergent Validity for the SOBDA Questionnaire Measured as Correlations of the Baseline SOBDA Score With Participant-completed Modified Medical Research Council (mMRC) and Physician-completed mMRC Scores at Visit 2
Description	Convergent validity is defined as the ability of the SOBDA questionnaire to measure required information and was assessed by examining the relationship between the SOBDA score and the participant/physician-completed mMRC Dyspnea Scale assessments. The physician/participant rated the degree of the participant's dyspnea (trouble breathing) on the 5-point mMRC scale (0, none; 4, very severe). Spearman's rank correlation coefficient assesses if the relationship between two variables is monotone. A correlation of +1 or -1 will occur if one variable is a perfect monotone of the other.
Time Frame	Baseline (last week of the 2-week Run-in Period) and pre-treatment on Visit 2 (Day 1 of the 6-week Treatment Period)

Outcome Measure Data

Analysis Population Description

Run-in Population. Participants with a SOBDA Baseline score and the indicated assessment at Visit 2 were analyzed. One participant who rated their own trouble breathing had missing data for the physician assessment.

Arm/Group Title	All Participants: 2-week Run-in Period
Arm/Group Description	All participants in the 2-week Run-in Period. Participants were permitted to use albuterol and/or ipratropium as rescue medication during this period.
Measure Participants	340
Physician-completed mMRC, n=339	0.24
Participant-completed mMRC, n=340	0.29

4. Primary Outcome

Title	Convergent Validity for the SOBDA Questionnaire Measured as the Correlation of the Baseline SOBDA Score With the Clinician Global Assessment of Dyspnea Severity (CGI-S) Score at Visit 2
Description	Convergent validity is defined as the ability of the SOBDA questionnaire to measure the required information and was assessed by examining the relationship between the SOBDA score with the CGI-S score. Spearman's rank correlation coefficient assesses if the relationship between two variables is monotone. A correlation of +1 or -1 will occur if one variable is a perfect monotone of the other. Clinicians were asked to assess the severity of the participant's dyspnea on the CGI-S scale. This was evaluated on a 1-4 Likert scale: 1 (mild) to 4 (very severe).
Time Frame	Baseline (last week of the 2-week Run-in Period) and pre-treatment on Visit 2 (Day 1 of the 6-week Treatment Period)

Outcome Measure Data

Analysis Population Description

Run-in Population. Participants with a SOBDA Baseline score and the indicated assessment at Visit 2 were analyzed.

Arm/Group Title	All Participants: 2-week Run-in Period
Arm/Group Description	All participants in the 2-week Run-in Period. Participants were permitted to use albuterol and/or ipratropium as rescue medication during this period.
Measure Participants	338
Number [Spearman rank correlation coefficient]	0.24

5. Primary Outcome

Title	Convergent Validity (CV) for the SOBDA Questionnaire Measured as the Correlation of the Baseline SOBDA Score With the Chronic Respiratory Disease Questionnaire-Self-Administered Standardized (CRQ-SAS) Dyspnea Domain Score at Visit 2
Description	Convergent validity is defined as the ability of the SOBDA questionnaire to measure required information and was assessed by examining the relationship between the SOBDA score and the CRQ-SAS dyspnea domain score. Pearson's correlation coefficient is a measure of the linear dependence between 2 variables. A correlation of +1 or -1 will occur if the data from the 2 variables lie exactly on a line. The CRQ is a 20-item instrument measuring 4 domains (each measured on a scale of 1 [maximum impairment] to 7 [no impairment]) of functioning: mastery, fatigue, emotional function, and dyspnea.
Time Frame	Baseline (last week of the 2-week Run-in Period) and pre-treatment on Visit 2 (Day 1 of the 6-week Treatment Period)

Outcome Measure Data

Analysis Population Description

Run-in Population. Participants with a SOBDA Baseline score and the indicated assessment at Visit 2 were analyzed.

Arm/Group Title	All Participants: 2-week Run-in Period
Arm/Group Description	All participants in the 2-week Run-in Period. Participants were permitted to use albuterol and/or ipratropium as rescue medication during this period.
Measure Participants	340
Number [Pearson's correlation coefficient]	-0.68

6. Primary Outcome

Title	Known Group Validity for the SOBDA Questionnaire Measured as the Comparison of the Baseline SOBDA Score in the Indicated Categories of the Physician-completed (PyC) mMRC Score at Visit 2
Description	SOBDA known group validity refers to the extent to which scores from the SOBDA questionnaire should differentiate participants with varying levels of dyspnea severity. It was assessed by comparing summary measures for the SOBDA score for each indicated level (0, 1, 2, 3, and 4) of the PyC mMRC. The physician rated the degree of the participant's dyspnea on the 5-point mMRC scale: 0 (none) to 4 (very severe). Known group validity was confirmed if the SOBDA score increased with increasing values of PyC mMRC, both indicating increased levels of breathlessness.
Time Frame	Baseline (last week of the 2-week Run-in Period) and pre-treatment on Visit 2 (Day 1 of the 6-week Treatment Period)

Outcome Measure Data

Analysis Population Description

Run-in Population. Participants with a SOBDA Baseline score and the Physician-completed mMRC score at Visit 2 were analyzed.

Arm/Group Title	All Participants: 2-week Run-in Period
Arm/Group Description	All participants in the 2-week Run-in Period. Participants were permitted to use albuterol and/or ipratropium as rescue medication during this period.
Measure Participants	339
PyC mMRC: 0 to 1, n=12	1.78 (0.196)
PyC mMRC: 2, n=200	2.08 (0.048)
PyC mMRC: 3, n=117	2.28 (0.063)
PyC mMRC: 4, n=10	2.73 (0.216)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis of covariance (ANCOVA) adjusted for age, gender, and percent predicted Forced Expiratory volume in one second (FEV1) at Screening.
	Method	ANCOVA
	Comments

7. Primary Outcome

Title	Known Group Validity for the SOBDA Questionnaire Measured as the Comparison of the Baseline SOBDA Score in the Indicated Categories of the Participant-completed (ParC) mMRC Score at Visit 2
Description	SOBDA known group validity refers to the extent to which scores from the SOBDA questionnaire should differentiate participants with varying levels of dyspnea severity. It was assessed by comparing summary measures for the SOBDA score for each indicated level (0, 1, 2, 3, and 4) of the ParC mMRC. The participant rated the degree of his/her dyspnea on the 5-point mMRC scale: 0 (none) to 4 (very severe). Known group validity was confirmed if the SOBDA score increased with increasing values of ParC mMRC, both indicating increased levels of breathlessness.
Time Frame	Baseline (last week of the 2-week Run-in Period) and pre-treatment on Visit 2 (Day 1 of the 6-week Treatment Period)

Outcome Measure Data

Analysis Population Description

Run-in Population. Participants with a SOBDA Baseline score and the Participant-completed mMRC score at Visit 2 were analyzed.

Arm/Group Title	All Participants: 2-week Run-in Period
Arm/Group Description	All participants in the 2-week Run-in Period. Participants were permitted to use albuterol and/or ipratropium as rescue medication during this period.
Measure Participants	340
ParC mMRC: 0, n=12	1.92 (0.192)
ParC mMRC: 1, n=103	1.94 (0.066)
ParC mMRC: 2, n=138	2.20 (0.056)
ParC mMRC: 3, n=65	2.26 (0.083)
ParC mMRC: 4, n=22	2.73 (0.142)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	ANCOVA adjusted for age, gender, and percent predicted FEV1 at Screening.
	Method	ANCOVA
	Comments

8. Primary Outcome

Title	Known Group Validity (KGV) for the SOBDA Questionnaire Measured as the Comparison of the Baseline SOBDA Score in the Indicated Categories of CGI-S Scores at Visit 2
Description	SOBDA KGV refers to the extent to which scores from the SOBDA questionnaire should differentiate participants with varying levels of dyspnea severity. It was assessed by comparing summary measures for the SOBDA score for each indicated level (0, 1, 2, 3, and 4) of the CGI-S score. Clinicians were asked to assess the severity of the participant's dyspnea on the CGI-S scale. This was evaluated on a 1-4 Likert scale: 1 (mild) to 4 (very severe). KGV was confirmed if the SOBDA score increased with increasing values of CGI-S, both indicating increased levels of breathlessness.
Time Frame	Baseline (last week of the 2-week Run-in Period) and pre-treatement on Visit 2 (Day 1 of the 6-week Treatment Period)

Outcome Measure Data

Analysis Population Description

Run-in Population. Participants with a SOBDA Baseline score and the CGI-S score at Visit 2 were analyzed.

Arm/Group Title	All Participants: 2-week Run-in Period
Arm/Group Description	All participants in the 2-week Run-in Period. Participants were permitted to use albuterol and/or ipratropium as rescue medication during this period.
Measure Participants	338
CGI-S: 1, n=19	1.87 (0.156)
CGI-S: 2, n=236	2.11 (0.045)
CGI-S: 3, n=78	2.33 (0.080)
CGI-S: 4, n=5	2.72 (0.305)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	ANCOVA adjusted for age, gender, and percent predicted FEV1 at Screening
	Method	ANCOVA
	Comments

9. Primary Outcome

Title	Participants (Par.) Classified as Responders/Non-responders According to the Patient Global Assessment of Change (PGAC) Response at Days 8, 15, 22, 29, 36, and 43 and at Visit 3/Premature Discontinuation (PD) (the End of the 6-week Treatment Period or PD)
Description	The PGAC is par. completed on a 1-5 scale: 1, much worse; 2, worse; 3, no change; 4, better; 5, much better. Responders were defined as par. with a rating of "better" or "much better" (score of 4 or 5) on the PGAC at the relevant week; non-responders were defined as par. with a response of "much worse," "worse," or "no change" on the PGAC. As pre-specified in the study protocol, results are presented independent of treatment allocation . The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.
Time Frame	Days 8, 15, 22, 29, 36, and 43 and Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (MITT) Population: all participants randomized to treatment who received at least one dose of study medication. Analyses were conducted on data available for each specified time point.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	303
Responders, Day 8 (Baseline to Week 1), n=293	105 140%
Non-responders, Day 8 (Baseline to Week 1), n=293	188 250.7%
Responders, Day 15 (Week 1 to Week 2), n=303	91 121.3%
Non-responders, Day 15 (Week 1 to Week 2), n=303	212 282.7%
Responders, Day 22 (Week 2 to Week 3), n=299	83 110.7%
Non-responders, Day 22 (Week 2 to Week 3), n=299	216 288%
Responders, Day 29 (Week 3 to Week 4), n=285	62 82.7%
Non-responders, Day 29 (Week 3 to Week 4), n=285	223 297.3%
Responders, Day 36 (Week 4 to Week 5), n=277	77 102.7%
Non-responders, Day 36 (Week 4 to Week 5), n=277	200 266.7%
Responders, Day 43 (Week 5 to Week 6), n=119	31 41.3%
Non-responders, Day 43 (Week 5 to Week 6), n=119	88 117.3%
Responders, Last Treatment Week, n=151	45 60%
Non-responders, Visit 3/PD, n=151	106 141.3%

10. Primary Outcome

Title	Change From the Previous Week to the Current Week's SOBDA Score by Participant-completed PGAC Response at Days 8, 15, 22, 29, 36, and 43 and at Visit 3/PD (End of the 6-week Treatment Period or PD)
Description	Responsiveness reflects the ability of the SOBDA questionnaire to detect change under conditions of known change. Responders (Rs)=participants (par.) with a rating of "better"/"much better" (score of 4/5) on the PGAC (range; 1 [much worse] to 5 [much better]) at the relevant week; NRs=par. with a response of "much worse," "worse," or "no change" (score of 3). Mean difference between Rs and NRs in the change from the previous week to the current week's SOBDA score was calculated. For Visit 3/PD, the change from Baseline to the last treatment week's SOBDA score for Rs and NRs was calculated.
Time Frame	Baseline; Days 8, 15, 22, 29, 36, and 43 and Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation. The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	223
Baseline to Day 8, responders, n=105	-0.26 (0.324)
Baseline to Day 8, non-responders, n=188	-0.01 (0.254)
Day 8 to Day 15, responders, n=91	-0.10 (0.280)
Day 8 to Day 15, non-responders, n=212	0.01 (0.222)
Day 15 to Day 22, responders, n=83	-0.08 (0.223)
Day 15 to Day 22, non-responders, n=216	0.02 (0.183)
Day 22 to Day 29, responders, n=62	-0.09 (0.198)
Day 22 to Day 29, non-responders, n=223	0.01 (0.193)
Day 29 to Day 36, responders, n=77	-0.07 (0.245)
Day 29 to Day 36, non-responders, n=200	0.03 (0.169)
Day 36 to Day 43, responders, n=31	-0.04 (0.167)
Day 36 to Day 43, non-responders, n=88	0.02 (0.240)
Baseline to Visit 3/PD, responders, n=45	-0.21 (0.497)
Baseline to Visit 3/PD, non-responders, n=106	-0.14 (0.423)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; difference between responders and non-responders during Week prior to Day 8
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.24
	Confidence Interval	() 95%; 0.18 to 0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; difference between responders and non-responders during Week prior to Day 15
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.12
	Confidence Interval	() 95%; 0.06 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; difference between responders and non-responders during Week prior to Day 22
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.11
	Confidence Interval	() 95%; 0.06 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; difference between responders and non-responders during Week prior to Day 29
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.11
	Confidence Interval	() 95%; 0.06 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; difference between responders and non-responders during Week prior to Day 36
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.13
	Confidence Interval	() 95%; 0.08 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.180
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; difference between responders and non-responders during Week prior to Day 43
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	() 95%; -0.03 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.307
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; difference between responders and non-responders during Week prior to Visit 3/PD
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	() 95%; -0.07 to 0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Primary Outcome

Title	Number of Participants Classified as Responders and Non-responders by Clinician Global Impression of Change Question (CGI-C) Response at Visit 3/PD
Description	Clinicians were asked to provide their clinical impression regarding change in the participant's shortness of breath by CGI-C. This was evaluated on a 1-5 Likert scale: 1 (much worse) to 5 (much better), with 3 being no change. A CGI-C responder was defined as a participant who had a response of "better" (4) or "much better" (5), and a non-responder was defined as a participant who had a response of "much worse" (1), "worse" (2), or "no change" (3).
Time Frame	Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation. The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	301
Responders	120 160%
Non-responders	181 241.3%

12. Primary Outcome

Title	Number of Participants Classified as Responders and Non-responders by CRQ-SAS Dyspnea Domain Response at Visit 3/PD
Description	A CRQ-SAS dyspnea domain responder was defined as a participant who had a score increase of 0.5 units or more for the dyspnea domain of the CRQ-SAS between Visit 2 and Visit 3/Premature Discontinuation. A non-responder was defined as a participant who had a decrease in the score, or an increase of less than 0.5 units.
Time Frame	Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation. The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	301
Responders	117 156%
Non-responders	184 245.3%

13. Primary Outcome

Title	Number of Participants Classified as Responders and Non-responders by Physician-completed and Participant-completed mMRC Response at Visit 3/PD
Description	A Physician-completed and Participant-completed mMRC responder was defined as a participant who had a score decrease of one unit or more between Visit 2 and Visit 3/Premature Discontinuation. A non-responder was defined as a participant who had the same score or an increase in score.
Time Frame	Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation. The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	301
Physician-completed mMRC responders	91 121.3%
Physician-completed mMRC non-responders	210 280%
Participant-completed mMRC responders	92 122.7%
Participant-completed mMRC non-responders	209 278.7%

14. Primary Outcome

Title	Change From Baseline to Last Treatment Week in the SOBDA Score by CGI-C Responses at Visit 3/PD
Description	The responsiveness of the SOBDA questionnaire was assessed by comparing score changes between responders and non-responders. The CGI-C is clinician completed on a 1 to 5 scale: 1, much worse; 2, worse; 3, no change; 4, better; 5, much better. Changes in mean SOBDA scores during the last week of treatment in responders and non-responders using definitions based on the CGI-C conducted at Visit 3/Premature Discontinuation were assessed.
Time Frame	Baseline (2-week Run-in Period) and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation. The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	301
Responders, n=120	-0.25 (0.484)
Non-responders, n=181	-0.03 (0.413)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; comparision of mean SOBDA score for CGI-C responders and non-responders
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.24
	Confidence Interval	() 95%; 0.14 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Primary Outcome

Title	Change From Baseline to Last Treatment Week in the SOBDA Score by CRQ-SAS Dyspnea Domain (DD) Responses at Visit 3/PD
Description	The responsiveness of the SOBDA questionnaire was assessed by comparing score changes of responders (Rs) versus non-responders (NRs). The CRQ-SAS DD includes 5 questions (q.) scored 1 (maximum impairment) to 7 (no impairment). Individual q. were equally weighted, and domain scores (DSs) (range=1-7) were calculated as the mean across the non-missing items within each domain (DSs were calculated although an individual item score was missing). Changes in mean SOBDA scores during the last treatment week in Rs and NRs using definitions based on the CRQ-SAS DD conducted at Visit 3/PD were assessed.
Time Frame	Baseline (2-week Run-in Period) and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation. The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	301
Responders, n=117	-0.32 (0.446)
Non-responders, n=184	0.01 (0.416)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; comparision of mean SOBDA score for CRQ-SAS Dyspnea Domain responders and non-responders
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; 0.21 to 0.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Primary Outcome

Title	Change From Baseline to Last Treatment Week in the SOBDA Score by Physician-completed mMRC and Participant-completed mMRC Responses at Visit 3/PD
Description	The responsiveness of the SOBDA questionnaire was assessed by comparing score changes between responders and non-responders. The mMRC ranges from 0 (no breathlessness except with strenous exercise) to 4 (too breathless to leave the house; breathless when dressing/undressing) and is completed by the clinician or the participant as indicated. Changes in mean SOBDA scores during the last week of treatment in responders and non-responders using definitions based on the Physician-completed (Ph-C) and Participant-completed (Pa-C) mMRC conducted at Visit 3/Premature Discontinuation were assessed.
Time Frame	Baseline (2-week Run-in Period) and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation. The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	301
Ph-C mMRC, responders, n=91	-0.13 (0.416)
Ph-C mMRC, non-responders, n=210	-0.11 (0.472)
Pa-C mMRC, responders, n=92	-0.18 (0.508)
Pa-C mMRC, non-responders, n=209	-0.09 (0.428)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.535
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; comparision of mean SOBDA score for Physician-Completed mMRC responders and non-responders
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.03
	Confidence Interval	() 95%; -0.08 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	All Participants: 2-week Run-in Period
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments	ANCOVA adjusted for age, gender, and SOBDA Baseline score; comparison of mean SOBDA score for Participant-Completed mMRC responders and non-responders
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	() 95%; -0.02 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Primary Outcome

Title	SOBDA Threshold for Response Assessed as Mean Change From the Previous Week's SOBDA Score Based on a Participant-completed PGAC Score Rated of "Better"
Description	Changes from Baseline in the SOBDA score for responders (Rs) and non-responders (NRs) (using the PGAC assessment; 1 [much worse] to 5 [much better]), together with the cumulative proportions of Rs and NRs, was used to establish the threshold for defining SOBDA questionnaire Rs. The threshold of response is a score change in the SOBDA questionnaire that is demonstrated to have a perceivable benefit for the participant. The threshold of response was evaluated as the change from Baseline in the SOBDA score based on PGAC scores pre-specified as "better" or demonstrating meaningful improvement.
Time Frame	Baseline (last week of the 2-week Run-in Period) and Weeks 1, 2, 3, 4, 5, and 6 (6-week Treatment Period)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation . The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	97
Baseline to Week 1, n=97	-0.26 (0.325)
Week 1 to Week 2, n=82	-0.08 (0.219)
Week 2 to Week 3, n=70	-0.08 (0.216)
Week 3 to Week 4, n=49	-0.10 (0.216)
Week 4 to Week 5, n=66	-0.08 (0.255)
Week 5 to Week 6, n=26	-0.05 (0.181)

18. Primary Outcome

Title	SOBDA Threshold for Response as Assessed by Mean Change From Baseline to the Last Treatment Week in the SOBDA Score Based on a CGI-C Response Rated as "Better"
Description	The threshold of response is a score change in the SOBDA questionnaire that is demonstrated to have a perceivable benefit for the participant. The threshold of response was evaluated as the change from Baseline in the SOBDA score based on CGI-C scores pre-specified as "better" or demonstrating meaningful improvement. The CGI-C is clinician completed on a 1 to 5 scale: 1, much worse, 2, worse; 3, no change; 4, better; 5, much better.
Time Frame	Baseline and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation. The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	109
Mean (Standard Deviation) [Scores on a scale]	-0.25 (0.484)

19. Primary Outcome

Title	SOBDA Threshold for Response as Assessed by Mean Change From Baseline to the Last Treatment Week in the SOBDA Score Based on a CRQ-SAS Dyspnea Domain (DD) Response Rated as "Better"
Description	The threshold of response (TOR) is a score change in the SOBDA questionnaire that is demonstrated to have a perceivable benefit. The TOR was evaluated as the change from Baseline in the SOBDA score based on CRQ-SAS scores pre-specified as "better" or demonstrating meaningful improvement. The CRQ-SAS DD includes 5 questions (q.) scored 1 (maximum impairment) to 7 (no impairment). Individual q. were equally weighted, and domain scores (DSs) (range=1-7) were calculated as the mean across the non-missing items within each domain (DSs were calculated although an individual item score was missing).
Time Frame	Baseline and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation. The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	68
Mean (Standard Deviation) [Scores on a scale]	-0.13 (0.417)

20. Primary Outcome

Title	SOBDA Threshold for Response Assessed as Mean Change From Baseline to Last Treatment Week in the SOBDA Score Based on Forced Expiratory Volume in One Second (FEV1) Change From Baseline of 50 Milliliters (mL) to <100 mL
Description	FEV1 response was rated as 1=No change or worse (i.e., change of <50 mL); 2=Better (i.e., change of 50 to <100 mL); 3=Much better (i.e., change of >=100 mL). The threshold of response is a score change in the SOBDA questionnaire that is demonstrated to have a perceivable benefit for the participant. The threshold of response was evaluated as the change from Baseline in the SOBDA score based on study assessment (FEV1) scores pre-specified as "better" or demonstrating meaningful improvement.
Time Frame	Baseline and Week Prior to Visit 3/PD (end of 6-week Treatment Period or earlier up to Week 8)

Outcome Measure Data

Analysis Population Description

MITT Population. Analyses were conducted on data available for each specified time point. As pre-specified in the study protocol, results are presented independent of treatment allocation. The study objectives were to assess the measurement properties and validity of the SOBDA questionnaire independent of specific treatment effect.

Arm/Group Title	MITT Population: 6-Week Treatment Period
Arm/Group Description	Participants randomized to receive FSC 250/50 mcg BID, SAL 50 mcg BID, or placebo BID for the 6-week Treatment Period comprising the MITT Population
Measure Participants	42
Mean (Standard Deviation) [mL]	-0.16 (0.492)

Adverse Events

Adverse Event Reporting Description	Safety data are presented for the Modified Intent-to-Treat (MITT) Population, comprised of all participants randomized to treatment who received at least one dose of study medication. Data summaries and analyses were based on the actual treatment received. One participant in the SAL 50 mcg arm was randomized but did not receive treatment.
Arm/Group Title	Placebo		SAL 50 mcg		FSC 250/50 mcg
Arm/Group Description	Matching placebo via DISKUS, administered as one inhalation twice daily (BID)		Salmeterol xinafoate (SAL) 50 micrograms (mcg) per inhalation via DISKUS, administered as one inhalation BID		Fluticasone propionate and salmeterol xinafoate fixed dose combination product (FSC) 250/50 mcg per inhalation via DISKUS, administered as one inhalation BID during the 6-week Double-blind Treatment Period
All Cause Mortality
	Placebo		SAL 50 mcg		FSC 250/50 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		SAL 50 mcg		FSC 250/50 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/75 (5.3%)		5/151 (3.3%)		3/139 (2.2%)
Cardiac disorders
Myocardial Infarction	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Gastrointestinal disorders
Impaired Gastric Emptying	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
General disorders
Chest Pain	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Infections and infestations
Pneumonia	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Metabolism and nutrition disorders
Dehydration	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Diabetes Mellitus Inadequate Control	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Nervous system disorders
Cerebrovascular Accident	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Psychiatric disorders
Suicide Attempt	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	4/75 (5.3%)		2/151 (1.3%)		0/139 (0%)
Acute Respiratory Failure	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Pneumothorax	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Respiratory Failure	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Other (Not Including Serious) Adverse Events
	Placebo		SAL 50 mcg		FSC 250/50 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/75 (18.7%)		34/151 (22.5%)		37/139 (26.6%)
Blood and lymphatic system disorders
Leukocytosis	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Cardiac disorders
Myocardial Infarction	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Ear and labyrinth disorders
Ear Pain	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Eye disorders
Vision Blurred	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Gastrointestinal disorders
Nausea	1/75 (1.3%)		2/151 (1.3%)		1/139 (0.7%)
Vomiting	0/75 (0%)		2/151 (1.3%)		1/139 (0.7%)
Diarrhea	0/75 (0%)		1/151 (0.7%)		1/139 (0.7%)
Dyspepsia	0/75 (0%)		1/151 (0.7%)		1/139 (0.7%)
Abdominal Discomfort	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Constipation	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Dry mouth	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Impaired Gastric Emptying	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Lip Swelling	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Melaena	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Stomatitis	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Toothache	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
General disorders
Chest Pain	1/75 (1.3%)		3/151 (2%)		0/139 (0%)
Adverse Drug Reaction	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Fatigue	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Irritability	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Edema Peripheral	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Pain	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Ankle Fracture	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Immune system disorders
Multiple Allergies	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Infections and infestations
Candidiasis	1/75 (1.3%)		0/151 (0%)		3/139 (2.2%)
Nasopharyngitis	1/75 (1.3%)		2/151 (1.3%)		1/139 (0.7%)
Bronchitis	0/75 (0%)		1/151 (0.7%)		1/139 (0.7%)
Gastroenteritis Viral	0/75 (0%)		1/151 (0.7%)		1/139 (0.7%)
Influenza	0/75 (0%)		1/151 (0.7%)		1/139 (0.7%)
Pneumonia	0/75 (0%)		2/151 (1.3%)		0/139 (0%)
Respiratory Tract Infection	2/75 (2.7%)		0/151 (0%)		0/139 (0%)
Acute Sinusitis	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Gastric Infection	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Pharyngitis	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Pneumonia Klebsiella	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Sinusitis	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Tracheobronchitis	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Upper Respiratory Tract Infection	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Viral Upper Respiratory Tract Infection	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Injury, poisoning and procedural complications
Hand Fracture	0/75 (0%)		1/151 (0.7%)		1/139 (0.7%)
Epicondylitis	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Joint Sprain	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Muscle Strain	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Investigations
Blood Pressure Increased	1/75 (1.3%)		0/151 (0%)		1/139 (0.7%)
Heart Rate Increased	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Metabolism and nutrition disorders
Hyperglycemia	1/75 (1.3%)		1/151 (0.7%)		0/139 (0%)
Hyperlipidemia	0/75 (0%)		2/151 (1.3%)		0/139 (0%)
Dehydration	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Diabetes Mellitus Inadequate Control	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Gout	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Hypokalemia	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	1/75 (1.3%)		1/151 (0.7%)		1/139 (0.7%)
Arthralgia	0/75 (0%)		0/151 (0%)		2/139 (1.4%)
Pain In Extremity	0/75 (0%)		0/151 (0%)		2/139 (1.4%)
Back pain	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Fibromyalgia	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Joint Swelling	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Lower Extremity Mass	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Muscle Spasms	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Musculoskeletal Chest Pain	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Musculoskeletal Pain	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Osteoarthritis	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung Neoplasm Malignant	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Seborrhoeic Keratosis	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Nervous system disorders
Headache	2/75 (2.7%)		6/151 (4%)		5/139 (3.6%)
Sinus Headache	0/75 (0%)		0/151 (0%)		3/139 (2.2%)
Carpal tunnel Syndrome	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Cerebrovascular Accident	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Dizziness	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Sciatica	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Syncope	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Psychiatric disorders
Anxiety	1/75 (1.3%)		2/151 (1.3%)		0/139 (0%)
Insomnia	1/75 (1.3%)		1/151 (0.7%)		0/139 (0%)
Depression	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Nervousness	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Suicide Attempt	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	4/75 (5.3%)		3/151 (2%)		0/139 (0%)
Dyspnea	2/75 (2.7%)		4/151 (2.6%)		1/139 (0.7%)
Cough	0/75 (0%)		3/151 (2%)		2/139 (1.4%)
Oropharyngeal Pain	0/75 (0%)		3/151 (2%)		0/139 (0%)
Sinus Congestion	0/75 (0%)		1/151 (0.7%)		2/139 (1.4%)
Respiratory Tract Congestion	0/75 (0%)		2/151 (1.3%)		0/139 (0%)
Acute Respiratory Failure	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Dysphonia	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Epistaxis	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Nasal Congestion	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Pneumothorax	0/75 (0%)		1/151 (0.7%)		0/139 (0%)
Respiratory Failure	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Rhinitis Allergic	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Rhinorrhea	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Skin and subcutaneous tissue disorders
Periorbital Edema	1/75 (1.3%)		0/151 (0%)		0/139 (0%)
Skin Lesion	0/75 (0%)		0/151 (0%)		1/139 (0.7%)
Vascular disorders
Hypertension	0/75 (0%)		0/151 (0%)		1/139 (0.7%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.