Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
COPD, Chronic Obstructive Pulmonary Disease, Efficacy, FEV1, Safety
Brief summary
The Purpose of this study is to assess the efficacy and safety of two strengths of the FF/GW642444 Inhalation Powder in subject with Chronic Obstructive Pulmonary Disease (COPD)
Interventions
Inhaled Corticosteroid (ICS)
Inhaled Corticosteroid (ICS)/ Long Acting Beta Agonist(LABA) for COPD
Long Acting Beta Agonist(LABA)
DRUGPlacebo
Placebo
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type of subject: outpatient * Informed consent: Subjects must give their signed and dated written informed consent to participate. * Gender: Male or female subjects A female is eligible to enter and participate in the study if she is of: * Non-child bearing potential OR * Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the acceptable contraceptive methods defined in the protocol * Age: ≥40 years of age at Screening (Visit 1) * COPD diagnosis: Subjects with a clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society \[Celli, 2004\] * Tobacco use: Subjects with a current or prior history of ≥10 pack-years of cigarette smoking at Screening (Visit 1). * Severity of Disease: Subjects with a Screening (Visit 1) measured post-albuterol/salbutamol: * FEV1/FVC ratio of ≤0.70 and * FEV1 ≤70% of predicted normal values * Dyspnea: Achieved a score of ≥2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Screening (Visit 1).
Exclusion criteria
Subjects meeting any of the following criteria must not be enrolled in the study: * Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study. * Asthma: Subjects with a current diagnosis of asthma * α1-antitrypsin deficiency: Subjects with α1-antitrypsin deficiency as the underlying cause of COPD * Other respiratory disorders: Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases, or other active pulmonary diseases * Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1) * Chest X-ray (or CT scan): Subjects with a chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. * Hospitalization: Subjects who are hospitalized due to poorly controlled COPD within 12 weeks of Visit 1. * Poorly controlled COPD: Subjects with poorly controlled COPD, defined as the occurrence of the following in the 6 weeks prior to Visit 1: Acute worsening of COPD that is managed by subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician. * Lower respiratory tract infection: Subjects with lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Visit 1. * Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular (i.e., pacemaker), neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled. * Peptic Ulcer disease: Subjects with clinically significant peptic ulcer disease that is uncontrolled. * Hypertension: Subjects with clinically significant hypertension that is uncontrolled. * Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis. * Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medication or components of the inhalation powder * Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years * Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol and/or their ipratropium 4 hours prior to spirometry testing at each study visit * Additional medication: Use of certain medications such as bronchodilators and corticosteroids for the protocol-specified times prior to Visit 1 (the Investigator will discuss the specific medications) * Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use (i.e., ≤12 hours per day) is not exclusionary. * Sleep apnea: Subjects with clinically significant sleep apnea who require use of continuous positive airway pressure (CPAP) device or non-invasive positive pressure ventilation (NIPPV) device. * Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Screening (Visit 1) or who will enter the acute phase of a Pulmonary Rehabilitation Program during the study. * Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits. * Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study. * Prior use of study medication/other investigational drugs * Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weighted Mean FEV1 Over 0-4 Hours (h) Post-dose at Day 168 | Baseline (BL) to Day 168 | Co-Primary Endpoint: Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Serial FEV1 measurements were taken electronically by spirometry at BL, weeks 2, 8, 12, and 84 (Day 168). Weighted mean (WM) was calculated using the 0 - 4 h post-dose FEV1 measurements that included the pre-dose (Day 1: 30 minutes \[min\] and 5 min prior to dosing; other serial visits:23 and 24 h after previous morning dose) and post-dose (5, 15, and 30 min and 1, 2, and 4 h) assessments. BL FEV1 is the mean of the two assessments made 30 and 5 min pre-dose at Day 1. WM change from BL was the WM at the visit minus the BL value. Analysis was performed using a repeated measures model with covariates of treatment, smoking status at screening (stratum), BL- mean of the two assessments made 30 and 5 min pre-dose on Day 1, centre grouping, Day, Day by BL and Day by treatment interactions. |
| Change From Baseline in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 169 | Baseline to Day 169 | Co-Primary Endpoint: Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 7, 14, 28, 56, 84, 112, 140, 168, and 169. BL was defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1.Trough FEV1 was defined as the mean of the FEV1 values obtained 23 and 24 hours after previous morning's dosing. Change from BL was calculated as the average at each visit minus the BL value. Analysis was performed using a repeated measures model with covariates of treatment, smoking status at screening (stratum), BL - mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Day 1, centre grouping, Day, Day by BL and Day by treatment interactions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Score at Day 168 | Baseline to Day 168 | Considered an 'Other' endpoint by FDA. CRQ-SAS measures 4 domains (mastery, fatigue, emotional function, and dyspnea) of functioning of participants with COPD: mastery (amount of control the participant feels he/she has over COPD symptoms); fatigue (how tired the participant feels); emotional function (how anxious/depressed the participant feels); and dyspnea (how short of breath the participant feels during physical activities). Each domain is measured on a scale of 1-7 (1=maximum impairment; 7=no impairment). Each domain score is calculated separately. Current assessment was done only for dyspnea domain. BL scores are the derived scores for each domain and total at Day 1 pre-dose. Change from BL was calculated as the average at each visit minus the BL value. Analysis performed used a repeated measures model with covariates of treatment, smoking status at screening (stratum), BL (derived scores at Day 1 pre-dose), centre grouping, Day, Day by BL and Day by treatment interactions. |
| Change From Baseline in Peak Post-dose FEV1 (0-4 Hour) on Day 1 | Baseline and Day 1 | Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. BL FEV1 is defined as the mean of the assessments made 30 minutes pre-dose and immediately pre-dose on Day 1. If one of these two assessments was missing then BL was defined as the single pre-dose FEV1 value on Day 1. Peak post-dose FEV1 (0-4 hours) is the maximum post-dose FEV1 recorded over the nominal timepoints of 5, 15 and 30 min, 1, 2 and 4 hours post the Day 1 dose. Change from BL is calculated as the peak post-dose FEV1 (0-4 hour) on Day 1 minus BL FEV1. Analysis performed used an Analysis of Covariance (ANCOVA) model with covariates of treatment, smoking status at screening (stratum), BL - mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Day 1, and centre grouping. |
| Time to Onset (Increase of 100 Milliliter [mL] From Baseline in 0-4 Hours Post-dose FEV1) on Treatment Day 1 | Baseline and Day 1 | Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Baseline FEV1 is defined as the mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Day 1. Time to onset on Treatment Day 1 is defined as a 100 mL increase from Baseline in FEV1. Time to increase of 100 mL from Baseline was calculated over the 5, 15, 30 minutes, and 1, 2, and 4 hours time points. A participant who had at least one post-dose FEV1 on Day 1, but did not achieve a 100 mL or more increase from Baseline at any scheduled time-point at which FEV1 was assessed up to and including 4 hours was censored. |
Countries
Argentina, Czechia, Germany, Japan, Poland, Romania, Russia, Ukraine, United States
Participant flow
Pre-assignment details
Eligible participants (par.) completed a 2-week single-blind (placebo) Run-in Period (RIP) to assess Baseline rescue use, symptoms, disease stability. Par. were then randomized to a 24-week Treatment Period. A total of 1909 par. were screened, 1577 entered the RIP, of whom 1226 were randomized, 1224 received at least one dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo OD in the morning from the DPI for 24 weeks. | 205 |
| FF 100 µg OD Participants received FF 100 µg OD in the morning from the DPI for 24 weeks. | 204 |
| FF 200 µg OD Participants received FF 200 µg OD in the morning from the DPI for 24 weeks. | 203 |
| VI 25 µg OD Participants received VI 25 µg OD in the morning from the DPI for 24 weeks. | 203 |
| FF/VI 100/25 µg OD Participants received FF/VI 100/25 µg OD in the morning from the DPI for 24 weeks. | 204 |
| FF/VI 200/25 µg OD Participants received FF/VI 200/25 µg OD in the morning from the DPI for 24 weeks. | 205 |
| Total | 1,224 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| 24-week, Double-blind Treatment Period | Adverse Event | 0 | 18 | 12 | 15 | 15 | 17 | 19 |
| 24-week, Double-blind Treatment Period | Lack of Efficacy-No Sub-Reason | 0 | 0 | 3 | 1 | 0 | 1 | 0 |
| 24-week, Double-blind Treatment Period | Lack of Efficacy-Sub-Reason Exacerbation | 0 | 12 | 2 | 5 | 11 | 7 | 7 |
| 24-week, Double-blind Treatment Period | Lost to Follow-up | 0 | 3 | 2 | 0 | 0 | 2 | 1 |
| 24-week, Double-blind Treatment Period | Physician Decision | 0 | 4 | 1 | 6 | 3 | 1 | 1 |
| 24-week, Double-blind Treatment Period | Protocol Defined Stopping Criteria | 0 | 7 | 12 | 7 | 7 | 15 | 12 |
| 24-week, Double-blind Treatment Period | Protocol Violation | 0 | 7 | 7 | 2 | 3 | 8 | 4 |
| 24-week, Double-blind Treatment Period | Study Closed/ Terminated | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
| 24-week, Double-blind Treatment Period | Withdrawal by Subject | 0 | 8 | 9 | 7 | 3 | 9 | 2 |
| 2-week, Single-blind Run-In Period | Adverse Event | 7 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-week, Single-blind Run-In Period | Did Not Meet Continuation Criteria | 246 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-week, Single-blind Run-In Period | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-week, Single-blind Run-In Period | Physician Decision | 6 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-week, Single-blind Run-In Period | Study Closed/Terminated | 68 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-week, Single-blind Run-In Period | Withdrawal by Subject | 23 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | FF 100 µg OD | FF 200 µg OD | VI 25 µg OD | FF/VI 100/25 µg OD | FF/VI 200/25 µg OD | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 61.9 Years STANDARD_DEVIATION 8.14 | 61.8 Years STANDARD_DEVIATION 8.28 | 61.8 Years STANDARD_DEVIATION 9.02 | 61.2 Years STANDARD_DEVIATION 8.62 | 61.9 Years STANDARD_DEVIATION 8.79 | 61.1 Years STANDARD_DEVIATION 8.67 | 61.6 Years STANDARD_DEVIATION 8.58 |
| Race/Ethnicity, Customized African American/African Heritage (HER) | 0 Participants | 2 Participants | 5 Participants | 3 Participants | 4 Participants | 2 Participants | 16 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Japanese/East Asian HER/South East Asian HER | 8 Participants | 5 Participants | 14 Participants | 4 Participants | 8 Participants | 11 Participants | 50 Participants |
| Race/Ethnicity, Customized White | 197 Participants | 197 Participants | 183 Participants | 196 Participants | 190 Participants | 192 Participants | 1155 Participants |
| Sex: Female, Male Female | 53 Participants | 54 Participants | 52 Participants | 52 Participants | 60 Participants | 68 Participants | 339 Participants |
| Sex: Female, Male Male | 152 Participants | 150 Participants | 151 Participants | 151 Participants | 144 Participants | 137 Participants | 885 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 39 / 205 | 32 / 204 | 46 / 203 | 43 / 203 | 36 / 204 | 40 / 205 |
| serious Total, serious adverse events | 10 / 205 | 6 / 204 | 10 / 203 | 16 / 203 | 12 / 204 | 15 / 205 |
Outcome results
Primary
Change From Baseline in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 169
Co-Primary Endpoint: Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 7, 14, 28, 56, 84, 112, 140, 168, and 169. BL was defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1.Trough FEV1 was defined as the mean of the FEV1 values obtained 23 and 24 hours after previous morning's dosing. Change from BL was calculated as the average at each visit minus the BL value. Analysis was performed using a repeated measures model with covariates of treatment, smoking status at screening (stratum), BL - mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Day 1, centre grouping, Day, Day by BL and Day by treatment interactions.
Time frame: Baseline to Day 169
Population: Intent-to-Treat (ITT) Population: all randomized par. who received at least one dose of study medication. Number of par. presented represent those with data available at the time point being presented; however, all par. in the ITT population without missing covariate information and with at least one post BL measurement are included in the analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 169 | 0.004 Liters | Standard Error 0.0189 |
| FF 100 µg OD | Change From Baseline in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 169 | 0.048 Liters | Standard Error 0.0187 |
| FF 200 µg OD | Change From Baseline in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 169 | 0.012 Liters | Standard Error 0.0185 |
| VI 25 µg OD | Change From Baseline in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 169 | 0.103 Liters | Standard Error 0.0185 |
| FF/VI 100/25 µg OD | Change From Baseline in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 169 | 0.148 Liters | Standard Error 0.0191 |
| FF/VI 200/25 µg OD | Change From Baseline in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1 at Day 169 | 0.135 Liters | Standard Error 0.0185 |
p-value: 0.09595% CI: [-0.008, 0.097]Mixed Models Analysis
p-value: 0.75695% CI: [-0.044, 0.06]Mixed Models Analysis
p-value: <0.00195% CI: [0.048, 0.151]Mixed Models Analysis
p-value: <0.00195% CI: [0.091, 0.197]Mixed Models Analysis
p-value: <0.00195% CI: [0.08, 0.183]Mixed Models Analysis
p-value: <0.00195% CI: [0.047, 0.152]Mixed Models Analysis
p-value: <0.00195% CI: [0.072, 0.174]Mixed Models Analysis
p-value: 0.09395% CI: [-0.008, 0.097]Mixed Models Analysis
p-value: 0.22495% CI: [-0.019, 0.083]Mixed Models Analysis
Primary
Change From Baseline in Weighted Mean FEV1 Over 0-4 Hours (h) Post-dose at Day 168
Co-Primary Endpoint: Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Serial FEV1 measurements were taken electronically by spirometry at BL, weeks 2, 8, 12, and 84 (Day 168). Weighted mean (WM) was calculated using the 0 - 4 h post-dose FEV1 measurements that included the pre-dose (Day 1: 30 minutes \[min\] and 5 min prior to dosing; other serial visits:23 and 24 h after previous morning dose) and post-dose (5, 15, and 30 min and 1, 2, and 4 h) assessments. BL FEV1 is the mean of the two assessments made 30 and 5 min pre-dose at Day 1. WM change from BL was the WM at the visit minus the BL value. Analysis was performed using a repeated measures model with covariates of treatment, smoking status at screening (stratum), BL- mean of the two assessments made 30 and 5 min pre-dose on Day 1, centre grouping, Day, Day by BL and Day by treatment interactions.
Time frame: Baseline (BL) to Day 168
Population: Intent-to-Treat (ITT) Population: all randomized par. who received at least one dose of study medication. Number of par. presented represent those with data available at the time point being presented; however, all par. in the ITT population without missing covariate information and with at least one post BL measurement are included in the analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Weighted Mean FEV1 Over 0-4 Hours (h) Post-dose at Day 168 | -0.012 Liters | Standard Error 0.0189 |
| FF 100 µg OD | Change From Baseline in Weighted Mean FEV1 Over 0-4 Hours (h) Post-dose at Day 168 | 0.034 Liters | Standard Error 0.0187 |
| FF 200 µg OD | Change From Baseline in Weighted Mean FEV1 Over 0-4 Hours (h) Post-dose at Day 168 | 0.029 Liters | Standard Error 0.0185 |
| VI 25 µg OD | Change From Baseline in Weighted Mean FEV1 Over 0-4 Hours (h) Post-dose at Day 168 | 0.173 Liters | Standard Error 0.0184 |
| FF/VI 100/25 µg OD | Change From Baseline in Weighted Mean FEV1 Over 0-4 Hours (h) Post-dose at Day 168 | 0.202 Liters | Standard Error 0.019 |
| FF/VI 200/25 µg OD | Change From Baseline in Weighted Mean FEV1 Over 0-4 Hours (h) Post-dose at Day 168 | 0.197 Liters | Standard Error 0.0184 |
p-value: 0.08595% CI: [-0.006, 0.098]Mixed Models Analysis
p-value: 0.12395% CI: [-0.011, 0.093]Mixed Models Analysis
p-value: <0.00195% CI: [0.133, 0.237]Mixed Models Analysis
p-value: <0.00195% CI: [0.161, 0.266]Mixed Models Analysis
p-value: <0.00195% CI: [0.157, 0.261]Mixed Models Analysis
p-value: <0.00195% CI: [0.116, 0.22]Mixed Models Analysis
p-value: <0.00195% CI: [0.117, 0.219]Mixed Models Analysis
p-value: 0.27495% CI: [-0.023, 0.081]Mixed Models Analysis
p-value: 0.35795% CI: [-0.027, 0.075]Mixed Models Analysis
Secondary
Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Score at Day 168
Considered an 'Other' endpoint by FDA. CRQ-SAS measures 4 domains (mastery, fatigue, emotional function, and dyspnea) of functioning of participants with COPD: mastery (amount of control the participant feels he/she has over COPD symptoms); fatigue (how tired the participant feels); emotional function (how anxious/depressed the participant feels); and dyspnea (how short of breath the participant feels during physical activities). Each domain is measured on a scale of 1-7 (1=maximum impairment; 7=no impairment). Each domain score is calculated separately. Current assessment was done only for dyspnea domain. BL scores are the derived scores for each domain and total at Day 1 pre-dose. Change from BL was calculated as the average at each visit minus the BL value. Analysis performed used a repeated measures model with covariates of treatment, smoking status at screening (stratum), BL (derived scores at Day 1 pre-dose), centre grouping, Day, Day by BL and Day by treatment interactions.
Time frame: Baseline to Day 168
Population: Intent-to-Treat (ITT) Population: all randomized par. who received at least one dose of study medication. Number of par. presented represent those with data available at the time point being presented; however, all par. in the ITT population without missing covariate information and with at least one post BL measurement are included in the analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Score at Day 168 | 0.21 Scores on a scale | Standard Error 0.077 |
| FF 100 µg OD | Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Score at Day 168 | 0.10 Scores on a scale | Standard Error 0.076 |
| FF 200 µg OD | Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Score at Day 168 | 0.21 Scores on a scale | Standard Error 0.075 |
| VI 25 µg OD | Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Score at Day 168 | 0.28 Scores on a scale | Standard Error 0.075 |
| FF/VI 100/25 µg OD | Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Score at Day 168 | 0.45 Scores on a scale | Standard Error 0.078 |
| FF/VI 200/25 µg OD | Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Score at Day 168 | 0.31 Scores on a scale | Standard Error 0.075 |
Secondary
Change From Baseline in Peak Post-dose FEV1 (0-4 Hour) on Day 1
Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. BL FEV1 is defined as the mean of the assessments made 30 minutes pre-dose and immediately pre-dose on Day 1. If one of these two assessments was missing then BL was defined as the single pre-dose FEV1 value on Day 1. Peak post-dose FEV1 (0-4 hours) is the maximum post-dose FEV1 recorded over the nominal timepoints of 5, 15 and 30 min, 1, 2 and 4 hours post the Day 1 dose. Change from BL is calculated as the peak post-dose FEV1 (0-4 hour) on Day 1 minus BL FEV1. Analysis performed used an Analysis of Covariance (ANCOVA) model with covariates of treatment, smoking status at screening (stratum), BL - mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Day 1, and centre grouping.
Time frame: Baseline and Day 1
Population: Intent-to-Treat (ITT) Population: all randomized participants who received at least one dose of study medication. Only those participants available at the indicated time point and without missing covariate information were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Peak Post-dose FEV1 (0-4 Hour) on Day 1 | 0.120 Liters | Standard Error 0.0108 |
| FF 100 µg OD | Change From Baseline in Peak Post-dose FEV1 (0-4 Hour) on Day 1 | 0.144 Liters | Standard Error 0.0109 |
| FF 200 µg OD | Change From Baseline in Peak Post-dose FEV1 (0-4 Hour) on Day 1 | 0.127 Liters | Standard Error 0.0109 |
| VI 25 µg OD | Change From Baseline in Peak Post-dose FEV1 (0-4 Hour) on Day 1 | 0.267 Liters | Standard Error 0.0109 |
| FF/VI 100/25 µg OD | Change From Baseline in Peak Post-dose FEV1 (0-4 Hour) on Day 1 | 0.272 Liters | Standard Error 0.0109 |
| FF/VI 200/25 µg OD | Change From Baseline in Peak Post-dose FEV1 (0-4 Hour) on Day 1 | 0.261 Liters | Standard Error 0.0108 |
Secondary
Time to Onset (Increase of 100 Milliliter [mL] From Baseline in 0-4 Hours Post-dose FEV1) on Treatment Day 1
Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Baseline FEV1 is defined as the mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Day 1. Time to onset on Treatment Day 1 is defined as a 100 mL increase from Baseline in FEV1. Time to increase of 100 mL from Baseline was calculated over the 5, 15, 30 minutes, and 1, 2, and 4 hours time points. A participant who had at least one post-dose FEV1 on Day 1, but did not achieve a 100 mL or more increase from Baseline at any scheduled time-point at which FEV1 was assessed up to and including 4 hours was censored.
Time frame: Baseline and Day 1
Population: Intent-to-Treat (ITT) Population: all randomized participants who received at least one dose of study medication. Only those participants available at the indicated time point were assessed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Onset (Increase of 100 Milliliter [mL] From Baseline in 0-4 Hours Post-dose FEV1) on Treatment Day 1 | NA Minutes |
| FF 100 µg OD | Time to Onset (Increase of 100 Milliliter [mL] From Baseline in 0-4 Hours Post-dose FEV1) on Treatment Day 1 | 231 Minutes |
| FF 200 µg OD | Time to Onset (Increase of 100 Milliliter [mL] From Baseline in 0-4 Hours Post-dose FEV1) on Treatment Day 1 | 242 Minutes |
| VI 25 µg OD | Time to Onset (Increase of 100 Milliliter [mL] From Baseline in 0-4 Hours Post-dose FEV1) on Treatment Day 1 | 17 Minutes |
| FF/VI 100/25 µg OD | Time to Onset (Increase of 100 Milliliter [mL] From Baseline in 0-4 Hours Post-dose FEV1) on Treatment Day 1 | 16 Minutes |
| FF/VI 200/25 µg OD | Time to Onset (Increase of 100 Milliliter [mL] From Baseline in 0-4 Hours Post-dose FEV1) on Treatment Day 1 | 17 Minutes |