Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Pulmonary Disease, Chronic Obstructive, Dyspnea
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.
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.
Interventions
Fluticasone propionate/salmeterol combination product 250/50mcg DISKUS twice a day for 8 weeks
DRUGSalmeterol
Salmeterol 50mcg DISKUS twice a day for 8 weeks
DRUGPlacebo
Placebo DISKUS twice a day for 8 weeks
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo via DISKUS, administered as one inhalation twice daily (BID) | 75 |
| SAL 50 mcg Salmeterol xinafoate (SAL) 50 micrograms (mcg) per inhalation via DISKUS, administered as one inhalation BID | 152 |
| FSC 250/50 mcg Fluticasone propionate and salmeterol xinafoate fixed dose combination product (FSC) 250/50 mcg per inhalation via DISKUS, administered as one inhalation BID | 139 |
| Albuterol and/or Ipratropium: Run-in Failure 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 | 52 |
| Total | 418 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 2-week Run-in Period | Adverse Event | 8 | 0 | 0 | 0 |
| 2-week Run-in Period | Did Not Meet Continuation Criteria | 14 | 0 | 0 | 0 |
| 2-week Run-in Period | Lost to Follow-up | 3 | 0 | 0 | 0 |
| 2-week Run-in Period | Physician Decision | 10 | 0 | 0 | 0 |
| 2-week Run-in Period | Protocol Violation | 5 | 0 | 0 | 0 |
| 2-week Run-in Period | Study Closed/Terminated | 2 | 0 | 0 | 0 |
| 2-week Run-in Period | Withdrawal by Subject | 10 | 0 | 0 | 0 |
| 6-week Double-blind Treatment Period | Adverse Event | 0 | 3 | 3 | 7 |
| 6-week Double-blind Treatment Period | Lack of Efficacy | 0 | 2 | 0 | 1 |
| 6-week Double-blind Treatment Period | Protocol Violation | 0 | 0 | 0 | 4 |
| 6-week Double-blind Treatment Period | Study Closed/Terminated | 0 | 0 | 1 | 0 |
| 6-week Double-blind Treatment Period | Withdrawal by Subject | 0 | 1 | 7 | 1 |
Baseline characteristics
| Characteristic | Placebo | SAL 50 mcg | FSC 250/50 mcg | Albuterol and/or Ipratropium: Run-in Failure | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.8 Years STANDARD_DEVIATION 9.82 | 60.1 Years STANDARD_DEVIATION 9.58 | 60.2 Years STANDARD_DEVIATION 9.45 | 63.8 Years STANDARD_DEVIATION 9.61 | 61.1 Years STANDARD_DEVIATION 9.65 |
| Race/Ethnicity, Customized African American/African Heritage | 9 participants | 12 participants | 12 participants | 8 participants | 41 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 65 participants | 140 participants | 127 participants | 44 participants | 376 participants |
| Sex: Female, Male Female | 29 Participants | 63 Participants | 60 Participants | 27 Participants | 179 Participants |
| Sex: Female, Male Male | 46 Participants | 89 Participants | 79 Participants | 25 Participants | 239 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 75 | 34 / 151 | 37 / 139 |
| serious Total, serious adverse events | 4 / 75 | 5 / 151 | 3 / 139 |
Outcome results
Primary
Change From Baseline to Last Treatment Week in the SOBDA Score by CGI-C Responses at Visit 3/PD
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants: 2-week Run-in Period | Change From Baseline to Last Treatment Week in the SOBDA Score by CGI-C Responses at Visit 3/PD | Responders, n=120 | -0.25 scores on a scale | Standard Deviation 0.484 |
| All Participants: 2-week Run-in Period | Change From Baseline to Last Treatment Week in the SOBDA Score by CGI-C Responses at Visit 3/PD | Non-responders, n=181 | -0.03 scores on a scale | Standard Deviation 0.413 |
p-value: <0.00195% CI: [0.14, 0.34]ANCOVA
Primary
Change From Baseline to Last Treatment Week in the SOBDA Score by CRQ-SAS Dyspnea Domain (DD) Responses at Visit 3/PD
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants: 2-week Run-in Period | Change From Baseline to Last Treatment Week in the SOBDA Score by CRQ-SAS Dyspnea Domain (DD) Responses at Visit 3/PD | Responders, n=117 | -0.32 Scores on a scale | Standard Deviation 0.446 |
| All Participants: 2-week Run-in Period | Change From Baseline to Last Treatment Week in the SOBDA Score by CRQ-SAS Dyspnea Domain (DD) Responses at Visit 3/PD | Non-responders, n=184 | 0.01 Scores on a scale | Standard Deviation 0.416 |
p-value: <0.00195% CI: [0.21, 0.4]ANCOVA
Primary
Change From Baseline to Last Treatment Week in the SOBDA Score by Physician-completed mMRC and Participant-completed mMRC Responses at Visit 3/PD
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants: 2-week Run-in Period | Change From Baseline to Last Treatment Week in the SOBDA Score by Physician-completed mMRC and Participant-completed mMRC Responses at Visit 3/PD | Ph-C mMRC, responders, n=91 | -0.13 Scores on a scale | Standard Deviation 0.416 |
| All Participants: 2-week Run-in Period | Change From Baseline to Last Treatment Week in the SOBDA Score by Physician-completed mMRC and Participant-completed mMRC Responses at Visit 3/PD | Ph-C mMRC, non-responders, n=210 | -0.11 Scores on a scale | Standard Deviation 0.472 |
| All Participants: 2-week Run-in Period | Change From Baseline to Last Treatment Week in the SOBDA Score by Physician-completed mMRC and Participant-completed mMRC Responses at Visit 3/PD | Pa-C mMRC, responders, n=92 | -0.18 Scores on a scale | Standard Deviation 0.508 |
| All Participants: 2-week Run-in Period | Change From Baseline to Last Treatment Week in the SOBDA Score by Physician-completed mMRC and Participant-completed mMRC Responses at Visit 3/PD | Pa-C mMRC, non-responders, n=209 | -0.09 Scores on a scale | Standard Deviation 0.428 |
p-value: 0.53595% CI: [-0.08, 0.15]ANCOVA
p-value: 0.0895% CI: [-0.02, 0.19]ANCOVA
Primary
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)
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants: 2-week Run-in Period | 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 to Day 8, responders, n=105 | -0.26 scores on a scale | Standard Deviation 0.324 |
| All Participants: 2-week Run-in Period | 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 to Day 8, non-responders, n=188 | -0.01 scores on a scale | Standard Deviation 0.254 |
| All Participants: 2-week Run-in Period | 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) | Day 8 to Day 15, responders, n=91 | -0.10 scores on a scale | Standard Deviation 0.28 |
| All Participants: 2-week Run-in Period | 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) | Day 8 to Day 15, non-responders, n=212 | 0.01 scores on a scale | Standard Deviation 0.222 |
| All Participants: 2-week Run-in Period | 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) | Day 15 to Day 22, responders, n=83 | -0.08 scores on a scale | Standard Deviation 0.223 |
| All Participants: 2-week Run-in Period | 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) | Day 15 to Day 22, non-responders, n=216 | 0.02 scores on a scale | Standard Deviation 0.183 |
| All Participants: 2-week Run-in Period | 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) | Day 22 to Day 29, responders, n=62 | -0.09 scores on a scale | Standard Deviation 0.198 |
| All Participants: 2-week Run-in Period | 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) | Day 22 to Day 29, non-responders, n=223 | 0.01 scores on a scale | Standard Deviation 0.193 |
| All Participants: 2-week Run-in Period | 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) | Day 29 to Day 36, responders, n=77 | -0.07 scores on a scale | Standard Deviation 0.245 |
| All Participants: 2-week Run-in Period | 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) | Day 29 to Day 36, non-responders, n=200 | 0.03 scores on a scale | Standard Deviation 0.169 |
| All Participants: 2-week Run-in Period | 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) | Day 36 to Day 43, responders, n=31 | -0.04 scores on a scale | Standard Deviation 0.167 |
| All Participants: 2-week Run-in Period | 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) | Day 36 to Day 43, non-responders, n=88 | 0.02 scores on a scale | Standard Deviation 0.24 |
| All Participants: 2-week Run-in Period | 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 to Visit 3/PD, responders, n=45 | -0.21 scores on a scale | Standard Deviation 0.497 |
| All Participants: 2-week Run-in Period | 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 to Visit 3/PD, non-responders, n=106 | -0.14 scores on a scale | Standard Deviation 0.423 |
p-value: <0.00195% CI: [0.18, 0.31]ANCOVA
p-value: <0.00195% CI: [0.06, 0.19]ANCOVA
p-value: <0.00195% CI: [0.06, 0.16]ANCOVA
p-value: <0.00195% CI: [0.06, 0.17]ANCOVA
p-value: <0.00195% CI: [0.08, 0.18]ANCOVA
p-value: 0.1895% CI: [-0.03, 0.15]ANCOVA
p-value: 0.30795% CI: [-0.07, 0.23]ANCOVA
Primary
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
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)
Population: Run-in Population. Participants with a SOBDA Baseline score and the indicated assessment at Visit 2 were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants: 2-week Run-in Period | 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 | -0.68 Pearson's correlation coefficient |
Primary
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
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)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants: 2-week Run-in Period | 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 | Physician-completed mMRC, n=339 | 0.24 Spearman rank correlation coefficient |
| All Participants: 2-week Run-in Period | 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 | Participant-completed mMRC, n=340 | 0.29 Spearman rank correlation coefficient |
Primary
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
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)
Population: Run-in Population. Participants with a SOBDA Baseline score and the indicated assessment at Visit 2 were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants: 2-week Run-in Period | 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 | 0.24 Spearman rank correlation coefficient |
Primary
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
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| All Participants: 2-week Run-in Period | 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 | 0.892 ratio of variance |
Primary
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
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)
Population: Run-in Population. Participants with a SOBDA Baseline score and the Participant-completed mMRC score at Visit 2 were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants: 2-week Run-in Period | 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 | ParC mMRC: 0, n=12 | 1.92 scores on a scale | Standard Error 0.192 |
| All Participants: 2-week Run-in Period | 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 | ParC mMRC: 1, n=103 | 1.94 scores on a scale | Standard Error 0.066 |
| All Participants: 2-week Run-in Period | 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 | ParC mMRC: 2, n=138 | 2.20 scores on a scale | Standard Error 0.056 |
| All Participants: 2-week Run-in Period | 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 | ParC mMRC: 3, n=65 | 2.26 scores on a scale | Standard Error 0.083 |
| All Participants: 2-week Run-in Period | 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 | ParC mMRC: 4, n=22 | 2.73 scores on a scale | Standard Error 0.142 |
p-value: <0.001ANCOVA
Primary
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
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)
Population: Run-in Population. Participants with a SOBDA Baseline score and the Physician-completed mMRC score at Visit 2 were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants: 2-week Run-in Period | 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 | PyC mMRC: 0 to 1, n=12 | 1.78 scores on a scale | Standard Error 0.196 |
| All Participants: 2-week Run-in Period | 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 | PyC mMRC: 2, n=200 | 2.08 scores on a scale | Standard Error 0.048 |
| All Participants: 2-week Run-in Period | 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 | PyC mMRC: 3, n=117 | 2.28 scores on a scale | Standard Error 0.063 |
| All Participants: 2-week Run-in Period | 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 | PyC mMRC: 4, n=10 | 2.73 scores on a scale | Standard Error 0.216 |
p-value: <0.001ANCOVA
Primary
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
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)
Population: Run-in Population. Participants with a SOBDA Baseline score and the CGI-S score at Visit 2 were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants: 2-week Run-in Period | 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 | CGI-S: 1, n=19 | 1.87 scores on a scale | Standard Error 0.156 |
| All Participants: 2-week Run-in Period | 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 | CGI-S: 2, n=236 | 2.11 scores on a scale | Standard Error 0.045 |
| All Participants: 2-week Run-in Period | 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 | CGI-S: 3, n=78 | 2.33 scores on a scale | Standard Error 0.08 |
| All Participants: 2-week Run-in Period | 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 | CGI-S: 4, n=5 | 2.72 scores on a scale | Standard Error 0.305 |
p-value: 0.008ANCOVA
Primary
Number of Participants Classified as Responders and Non-responders by Clinician Global Impression of Change Question (CGI-C) Response at Visit 3/PD
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)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants: 2-week Run-in Period | Number of Participants Classified as Responders and Non-responders by Clinician Global Impression of Change Question (CGI-C) Response at Visit 3/PD | Responders | 120 participants |
| All Participants: 2-week Run-in Period | Number of Participants Classified as Responders and Non-responders by Clinician Global Impression of Change Question (CGI-C) Response at Visit 3/PD | Non-responders | 181 participants |
Primary
Number of Participants Classified as Responders and Non-responders by CRQ-SAS Dyspnea Domain Response at Visit 3/PD
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)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants: 2-week Run-in Period | Number of Participants Classified as Responders and Non-responders by CRQ-SAS Dyspnea Domain Response at Visit 3/PD | Responders | 117 participants |
| All Participants: 2-week Run-in Period | Number of Participants Classified as Responders and Non-responders by CRQ-SAS Dyspnea Domain Response at Visit 3/PD | Non-responders | 184 participants |
Primary
Number of Participants Classified as Responders and Non-responders by Physician-completed and Participant-completed mMRC Response at Visit 3/PD
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)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants: 2-week Run-in Period | Number of Participants Classified as Responders and Non-responders by Physician-completed and Participant-completed mMRC Response at Visit 3/PD | Physician-completed mMRC responders | 91 participants |
| All Participants: 2-week Run-in Period | Number of Participants Classified as Responders and Non-responders by Physician-completed and Participant-completed mMRC Response at Visit 3/PD | Physician-completed mMRC non-responders | 210 participants |
| All Participants: 2-week Run-in Period | Number of Participants Classified as Responders and Non-responders by Physician-completed and Participant-completed mMRC Response at Visit 3/PD | Participant-completed mMRC responders | 92 participants |
| All Participants: 2-week Run-in Period | Number of Participants Classified as Responders and Non-responders by Physician-completed and Participant-completed mMRC Response at Visit 3/PD | Participant-completed mMRC non-responders | 209 participants |
Primary
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)
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)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants: 2-week Run-in Period | 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) | Responders, Day 8 (Baseline to Week 1), n=293 | 105 participants |
| All Participants: 2-week Run-in Period | 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) | Non-responders, Day 8 (Baseline to Week 1), n=293 | 188 participants |
| All Participants: 2-week Run-in Period | 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) | Responders, Day 15 (Week 1 to Week 2), n=303 | 91 participants |
| All Participants: 2-week Run-in Period | 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) | Non-responders, Day 15 (Week 1 to Week 2), n=303 | 212 participants |
| All Participants: 2-week Run-in Period | 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) | Responders, Day 22 (Week 2 to Week 3), n=299 | 83 participants |
| All Participants: 2-week Run-in Period | 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) | Non-responders, Day 22 (Week 2 to Week 3), n=299 | 216 participants |
| All Participants: 2-week Run-in Period | 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) | Responders, Day 29 (Week 3 to Week 4), n=285 | 62 participants |
| All Participants: 2-week Run-in Period | 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) | Non-responders, Day 29 (Week 3 to Week 4), n=285 | 223 participants |
| All Participants: 2-week Run-in Period | 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) | Responders, Day 36 (Week 4 to Week 5), n=277 | 77 participants |
| All Participants: 2-week Run-in Period | 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) | Non-responders, Day 36 (Week 4 to Week 5), n=277 | 200 participants |
| All Participants: 2-week Run-in Period | 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) | Responders, Day 43 (Week 5 to Week 6), n=119 | 31 participants |
| All Participants: 2-week Run-in Period | 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) | Non-responders, Day 43 (Week 5 to Week 6), n=119 | 88 participants |
| All Participants: 2-week Run-in Period | 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) | Responders, Last Treatment Week, n=151 | 45 participants |
| All Participants: 2-week Run-in Period | 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) | Non-responders, Visit 3/PD, n=151 | 106 participants |
Primary
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
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)
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants: 2-week Run-in Period | 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 | -0.25 Scores on a scale | Standard Deviation 0.484 |
Primary
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
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)
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants: 2-week Run-in Period | 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 | -0.13 Scores on a scale | Standard Deviation 0.417 |
Primary
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
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)
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants: 2-week Run-in Period | 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 | -0.16 mL | Standard Deviation 0.492 |
Primary
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
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants: 2-week Run-in Period | 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 to Week 1, n=97 | -0.26 scores on a scale | Standard Deviation 0.325 |
| All Participants: 2-week Run-in Period | 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 | Week 1 to Week 2, n=82 | -0.08 scores on a scale | Standard Deviation 0.219 |
| All Participants: 2-week Run-in Period | 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 | Week 2 to Week 3, n=70 | -0.08 scores on a scale | Standard Deviation 0.216 |
| All Participants: 2-week Run-in Period | 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 | Week 3 to Week 4, n=49 | -0.10 scores on a scale | Standard Deviation 0.216 |
| All Participants: 2-week Run-in Period | 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 | Week 4 to Week 5, n=66 | -0.08 scores on a scale | Standard Deviation 0.255 |
| All Participants: 2-week Run-in Period | 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 | Week 5 to Week 6, n=26 | -0.05 scores on a scale | Standard Deviation 0.181 |
Primary
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
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Participants: 2-week Run-in Period | 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 | 0.01 scores on a scale | Standard Deviation 0.244 |
p-value: 0.71395% CI: [-0.03, 0.05]t-test, 2 sided