Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Long acting muscarinic antagonist, Tiotropium, Chronic Bronchitis, Emphysema, Chronic Obstructive Pulmonary Disease
Brief summary
The purpose of this study is to further characterize the dose response of GSK573719 at doses of 15.6 micrograms (mcg) to 125 mcg once daily in patients with chronic obstructive pulmonary disease (COPD). Treatment with doses of GSK573719 dosed twice daily will also be included to further evaluate dosing frequency. Treatment with tiotropium (18 mcg) once daily via the Handihaler will be included as an active control. A placebo treatment will be included in order to evaluate absolute treatment effect of the different doses of GSK573719.
Detailed description
Inhaled bronchodilators, such as beta 2 agonists and anticholinergics, and inhaled corticosteroids are the mainstays of therapy in patients diagnosed with COPD. Anticholinergic bronchodilators or long acting muscarinic receptor antagonists function by blocking endogenous airway smooth muscle cholinergic tone. Treatment with anticholinergics has been shown to significantly improve forced expiratory volume in 1 second (FEV1), resting and dynamic lung hyperinflation, symptoms, and exercise capacity in patients with COPD. Currently tiotropium is the only approved long acting muscarinic antagonist available for treatment of COPD. This is a multicenter, randomized, double-blind, placebo controlled, three way crossover, incomplete block study to evaluate 4 doses of GSK573719 inhaled once daily and 2 doses of GSK573719 inhaled twice daily over 7 days in patients with COPD. Tiotropium will be included as an open label active comparator. A placebo treatment will be included to evaluate treatment effect of each GSK573719 dose. Pharmacokinetic profiles of GSK573719 will also be determined. Each eligible subject will receive a sequence of 3 of 8 potential treatments for a total of 3 treatment periods per subject. There will be 7 clinic visits, during three of which 24 hour serial spirometry will be performed. The total duration of subject participation is approximately 9 weeks.
Interventions
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Outpatient * A signed and dated written informed consent prior to study participation. * Male or female adults. * 40 to 80 years of age at Visit 1 * Diagnosis of COPD * Current or former cigarette smokers with a history of cigarette smoking of greater than or equal to 10 pack-years * Post-albuterol forced expiratory volume in 1 second (FEV1)/ forced vital capacity (FVC)\<0.70 and post albuterol FEV1 of greater than or equal to 35% and less than or equal to 70% of predicted normal values
Exclusion criteria
* Women who are pregnant or lactating or are planning on becoming pregnant during the study. * A current diagnosis of asthma * Known alpha-1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer * Other significant respiratory conditions in addition to COPD * Other diseases that are uncontrolled including cancer in remission for less than 5 years * Chest x-ray or CT scan with clinically significant abnormalities not believed to be due to the presence of COPD * Hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate * A medical condition that contraindicates study participation or use of an inhaled anticholinergic * Hospitalization for COPD or pneumonia within 12 weeks of Visit 1 * Any previous lung resection surgery * A body mass index (BMI) value of \>35 kilogram (kg)/meter squared (m2) * An abnormal and significant electrocardiogram finding at Visit 1 * Significantly abnormal finding from clinical chemistry or haematology tests at Visit 1. * A positive Hepatitis B surface antigen or positive Hepatitis C antibody * Medically unable to withhold albuterol (salbutamol) for the 6 hour period prior to study visits * Use of depot corticosteroids within 12 weeks of Visit 1 * Use of oral or parenteral corticosteroids or antibiotics for lower respiratory tract infection within 6 weeks of Visit 1 * Use of long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) product if LABA/ICS therapy is discontinued within 30 days of Visit 1 * Use of ICS at a dose of \>1000mcg/day of fluticasone propionate or equivalent within 30 days of Visit 1 * Initiation or discontinuation of ICS within 30 days of Visit 1 * Use of tiotropium or phosphodiesterase 4 inhibitors within 14 days of Visit 1 * Use of theophyllines, oral leukotriene inhibitors, long-acting oral beta-agonists, or inhaled long-acting beta-agonists within 48 hours of Visit 1 * Short-acting oral beta-agonists within 12 hours of Visit 1 * Use of LABA/ICS combination products only if discontinuing LABA therapy and switching to ICS monotherapy within 48 hours of Visit 1 for the LABA component * Use of sodium cromoglycate or nedocromil sodium within 24 hours of Visit 1 * Use of inhaled short-acting beta-agonists, inhaled short-acting anticholinergics, or inhaled short-acting anticholinergic/short-acting beta-agonist combination products within 6 hours of Visit 1 * Use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer) * Oxygen therapy prescribed for greater than 12 hours a day * Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators * Use of continuous positive airway pressure (CPAP), nocturnal positive pressure or non-invasive positive pressure ventilation (NIPPV), including use for sleep apnea. * Acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1 * A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1 * Anyone affiliated with investigator site * Previous use of GSK573719 or GSK53719/GW642444
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) | Day 7 and Day 8 of each treatment period (up to Study Day 50) | The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate trough FEV1dose response. The Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed separately and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. The fixed-effects parameters of the dose response model include Emax (the maximum predicted FEV1 response), ED50 (potency), and S0 (estimated Baseline FEV1). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Data for Emax and S0 are reported in this table. mITT=Modified Intent-to-Treat; par.=participants; BL=Baseline. |
| Final Dose-response Model for Trough FEV1 for ED50 (Potency) Parameter | Day 7 and Day 8 of each treatment period (up to Study Day 50) | The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate dose response. Both a Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. ED50 is defined as the potency and is the dose that yields 50% of Emax (maximum predicted FEV1 response). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. |
| Final Dose-response Model Parameter β-FEV1MB-S0 for Trough FEV1 | Day 7 and Day 8 of each treatment period (up to Study Day 50) | The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate dose response. Both a Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. β-FEV1MB-S0 is defined as the covariate (Baseline trough FEV1) effect on the mean Baseline trough FEV1 estimate (S0). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. |
| Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period | Baseline and Day 8 of each treatment period (up to Study Day 50) | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Treatment Day 8 is defined as the value obtained 24 hours after the morning dose administered on Day 7. Analysis was performed using a mixed model with covariates of mean Baseline, period Baseline, treatment, and period as fixed effects and participant as a random effect. Baseline is the FEV1 value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each particiapant. Change from Baseline for each treatment period is the trough FEV1 at Day 8 minus the Baseline value for that treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | Baseline and Day 7 of each treatment period (TP; up to Study Day 49) | Serial FEV1 for once daily dosing is recorded at the pre-AM dose (AMD; time 0 hour \[h\]) and at 1, 3, 6, 9, 12,13, 15, 23, and 24 hours after the AMD on Day 7. For twice daily dosing, the 12 h AMD corresponds to the pre-PM dose (PMD), the 13 h AMD corresponds to the 1 h PMD, the 15 h AMD corresponds to the 3 h PMD, the 23 h AMD corresponds to the 11 h PMD, and the 24 h AMD corresponds to the 12 h PMD in this table. Analysis was performed using a mixed model with covariates of mean BL, period BL, treatment, period, time, time by period BL interaction, time by mean BL interaction, and time by treatment interaction as fixed effects and participant as a random effect. BL is the value recorded pre-dose on Day 1 of each TP, mean BLis the mean of the BLs for each participant, and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each timepoint within a TP is the serial FEV1 measure at that timepoint minus the BL value for that TP. |
| Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period | Baseline and Day 7 of each treatment period (TP; up to Study Day 49) | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The weighted mean FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The weighted mean FEV1 was calculated using 0-24 hour post-dose measurements at Day 7 of each treatment period, which included pre-dose and post-dose 1, 3, 6, 9, 12, 13, 15, 23, and 24 hours. Analysis was performed using a mixed model with covariates of mean BL, period BL, treatment, and period as fixed effects and participant as a random effect. BL is the FEV1 value recorded pre-dose on Day 1 of each TP, mean BL is the mean of the BLs for each participant, and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each TP is the weighted mean FEV1 at Day 7 minus the BL value for that TP. |
Countries
United States
Participant flow
Pre-assignment details
Participants were randomized to receive a sequence of 3 of 8 possible treatments over 3 treatment periods. There are 56 combinations of 3 treatments from the 8 study treatments, each of which can be ordered in 6 ways (totaling 336 possible sequences; 163 were randomly assigned). Participant Flow data are presented by treatment rather than sequence.
Participants by arm
| Arm | Count |
|---|---|
| All Study Treatments Participants received a sequence containing 3 of the following 8 possible treatments: placebo; UMEC 15.6 µg, 31.25 µg, 62.5 µg, and 125 µg QD; UMEC 15.6 µg and 31.25 µg BID; TIO 18 µg QD. Participants received each of the treatments in 1 of 3 7-day treatment periods, each of which was followed by a Washout Period. Treatment Periods 1 and 2 were followed by a 10- to 14-day Washout Period; Treatment Period 3 was followed by a 7- to 9-day Washout Period before the follow-up phone call. | 163 |
| Total | 163 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 (7 Days) | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 |
| Treatment Period 1 (7 Days) | Lack of Efficacy | 1 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Treatment Period 1 (7 Days) | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Treatment Period 1 (7 Days) | Participant Withdrew Consent | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Treatment Period 3 (7 Days) | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 3 (7 Days) | Protocol Deviation | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Washout Period 1 (10-14 Days) | Participant Withdrew Consent | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Washout Period 2 (10-14 Days) | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Washout Period 2 (10-14 Days) | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Washout Period 2 (10-14 Days) | Participant Withdrew Consent | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | All Study Treatments |
|---|---|
| Age, Continuous | 59.5 Years STANDARD_DEVIATION 9.21 |
| Race/Ethnicity, Customized African American/African Heritage | 16 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants |
| Race/Ethnicity, Customized Mixed Race | 1 participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 145 participants |
| Sex: Female, Male Female | 85 Participants |
| Sex: Female, Male Male | 78 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 | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 60 | 3 / 60 | 0 / 57 | 0 / 59 | 8 / 60 | 4 / 56 | 1 / 58 | 2 / 56 |
| serious Total, serious adverse events | 0 / 60 | 1 / 60 | 1 / 57 | 0 / 59 | 0 / 60 | 0 / 56 | 0 / 58 | 0 / 56 |
Outcome results
Primary
Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 on Treatment Day 8 is defined as the value obtained 24 hours after the morning dose administered on Day 7. Analysis was performed using a mixed model with covariates of mean Baseline, period Baseline, treatment, and period as fixed effects and participant as a random effect. Baseline is the FEV1 value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each particiapant. Change from Baseline for each treatment period is the trough FEV1 at Day 8 minus the Baseline value for that treatment period.
Time frame: Baseline and Day 8 of each treatment period (up to Study Day 50)
Population: mITT Population. All participants with \>=1 post-baseline assessment and non-missing covariate data are included in the analysis. The number of participants represents participants who provided data at Day 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| All Study Treatments | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period | -0.074 Liters | Standard Error 0.022 |
| UMEC 15.6 µg QD | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period | 0.038 Liters | Standard Error 0.022 |
| UMEC 31.25 µg QD | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period | 0.027 Liters | Standard Error 0.023 |
| UMEC 62.5 µg QD | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period | 0.049 Liters | Standard Error 0.022 |
| UMEC 125 µg QD | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period | 0.109 Liters | Standard Error 0.022 |
| UMEC 15.6 µg BID | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period | 0.051 Liters | Standard Error 0.023 |
| UMEC 31.25 µg BID | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period | 0.065 Liters | Standard Error 0.023 |
| TIO 18 µg QD | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period | 0.027 Liters | Standard Error 0.023 |
p-value: <0.00195% CI: [0.058, 0.168]Mixed Models Analysis
p-value: <0.00195% CI: [0.045, 0.158]Mixed Models Analysis
p-value: <0.00195% CI: [0.068, 0.179]Mixed Models Analysis
p-value: <0.00195% CI: [0.127, 0.239]Mixed Models Analysis
p-value: <0.00195% CI: [0.069, 0.182]Mixed Models Analysis
p-value: <0.00195% CI: [0.083, 0.196]Mixed Models Analysis
p-value: <0.00195% CI: [0.045, 0.157]Mixed Models Analysis
Primary
Final Dose-response Model for Trough FEV1 for ED50 (Potency) Parameter
The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate dose response. Both a Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. ED50 is defined as the potency and is the dose that yields 50% of Emax (maximum predicted FEV1 response). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second.
Time frame: Day 7 and Day 8 of each treatment period (up to Study Day 50)
Population: mITT Population: par. randomized to treatment who received \>=1 dose of study medication. Par. with \>=1 post-BL assessment and non-missing covariate data are included in the analysis. Different par. may have been analyzed at different time points (n=X in category titles); the overall number of par. analyzed reflects everyone in the mITT Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| All Study Treatments | Final Dose-response Model for Trough FEV1 for ED50 (Potency) Parameter | Day 8, ED50, n=157 | 37.4 micrograms |
| All Study Treatments | Final Dose-response Model for Trough FEV1 for ED50 (Potency) Parameter | Pooled Day 7 and Day 8, ED50, n=160 | 38.2 micrograms |
Primary
Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1)
The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate trough FEV1dose response. The Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed separately and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. The fixed-effects parameters of the dose response model include Emax (the maximum predicted FEV1 response), ED50 (potency), and S0 (estimated Baseline FEV1). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Data for Emax and S0 are reported in this table. mITT=Modified Intent-to-Treat; par.=participants; BL=Baseline.
Time frame: Day 7 and Day 8 of each treatment period (up to Study Day 50)
Population: mITT Population: par. randomized to treatment who received \>=1 dose of study medication. Par. with \>=1 post-BL assessment and non-missing covariate data are included in the analysis. Different par. may have been analyzed at different time points (n=X in category titles); the overall number of par. analyzed reflects everyone in the mITT Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| All Study Treatments | Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) | Pooled Day 7 and Day 8, Emax, n=160 | 0.156 Liters |
| All Study Treatments | Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) | Pooled Day 7 and 8, S0, n=160 | 1.24 Liters |
| All Study Treatments | Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) | Day 8, Emax, n=157 | 0.185 Liters |
| All Study Treatments | Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) | Day 8, S0, n=157 | 1.24 Liters |
Primary
Final Dose-response Model Parameter β-FEV1MB-S0 for Trough FEV1
The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate dose response. Both a Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. β-FEV1MB-S0 is defined as the covariate (Baseline trough FEV1) effect on the mean Baseline trough FEV1 estimate (S0). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second.
Time frame: Day 7 and Day 8 of each treatment period (up to Study Day 50)
Population: mITT Population: par. randomized to treatment who received \>=1 dose of study medication. Par. with \>=1 post-BL assessment and non-missing covariate data are included in the analysis. Different par. may have been analyzed at different time points (n=X in category titles); the overall number of par. analyzed reflects everyone in the mITT Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Study Treatments | Final Dose-response Model Parameter β-FEV1MB-S0 for Trough FEV1 | Day 8, βFEV1MB-S0, n=157 | 0.691 fraction of mean estimated Baseline FEV1 |
| All Study Treatments | Final Dose-response Model Parameter β-FEV1MB-S0 for Trough FEV1 | Pooled Day 7 and 8, βFEV1MB-S0, n=160 | 0.686 fraction of mean estimated Baseline FEV1 |
p-value: <0.0001Wald Test
p-value: <0.0001Wald Test
Secondary
Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period
Serial FEV1 for once daily dosing is recorded at the pre-AM dose (AMD; time 0 hour \[h\]) and at 1, 3, 6, 9, 12,13, 15, 23, and 24 hours after the AMD on Day 7. For twice daily dosing, the 12 h AMD corresponds to the pre-PM dose (PMD), the 13 h AMD corresponds to the 1 h PMD, the 15 h AMD corresponds to the 3 h PMD, the 23 h AMD corresponds to the 11 h PMD, and the 24 h AMD corresponds to the 12 h PMD in this table. Analysis was performed using a mixed model with covariates of mean BL, period BL, treatment, period, time, time by period BL interaction, time by mean BL interaction, and time by treatment interaction as fixed effects and participant as a random effect. BL is the value recorded pre-dose on Day 1 of each TP, mean BLis the mean of the BLs for each participant, and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each timepoint within a TP is the serial FEV1 measure at that timepoint minus the BL value for that TP.
Time frame: Baseline and Day 7 of each treatment period (TP; up to Study Day 49)
Population: mITT Population. All participants (par.) with \>=1 post-BL assessment and non-missing covariate data are included in the analysis. Different par. may have been analyzed at different time points (n=X, X, X, X in the category titles), so the overall number of par. analyzed reflects everyone in the mITT Population with data available at \>=1 time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| All Study Treatments | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | Pre-AMD, n=59, 58, 55, 59, 60, 54, 57, 54 | -0.007 Liters | Standard Error 0.021 |
| All Study Treatments | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 9 h AMD, n=59, 59, 56, 59, 58, 55, 56, 56 | -0.072 Liters | Standard Error 0.022 |
| All Study Treatments | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 6 h AMD, n=59, 59, 55, 59, 59, 55, 57, 56 | -0.054 Liters | Standard Error 0.022 |
| All Study Treatments | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 1 h AMD, n=59, 59, 56, 59, 60, 55, 57, 56 | -0.006 Liters | Standard Error 0.023 |
| All Study Treatments | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 15 h AMD/3 h PMD, n=59, 58, 56, 58, 59, 55, 57, 56 | -0.112 Liters | Standard Error 0.023 |
| All Study Treatments | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 12 h AMD/Pre-PMD, n=59, 59, 56, 59, 59, 55, 57, 56 | -0.086 Liters | Standard Error 0.023 |
| All Study Treatments | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 13 h AMD/1 h PMD, n=59, 59, 56, 59, 58, 55, 57, 56 | -0.085 Liters | Standard Error 0.024 |
| All Study Treatments | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 3 h AMD, n=59, 59, 56, 59, 59, 55, 57, 56 | -0.013 Liters | Standard Error 0.024 |
| All Study Treatments | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 24 h AMD/12 h PMD, n=59, 58, 56, 59, 59, 55, 57,56 | -0.065 Liters | Standard Error 0.024 |
| All Study Treatments | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 23 h AMD/11 h PMD, n=59, 57, 56, 59, 59, 55, 57,56 | -0.101 Liters | Standard Error 0.024 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 3 h AMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.082 Liters | Standard Error 0.024 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | Pre-AMD, n=59, 58, 55, 59, 60, 54, 57, 54 | 0.068 Liters | Standard Error 0.021 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 6 h AMD, n=59, 59, 55, 59, 59, 55, 57, 56 | 0.056 Liters | Standard Error 0.022 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 9 h AMD, n=59, 59, 56, 59, 58, 55, 56, 56 | 0.040 Liters | Standard Error 0.022 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 1 h AMD, n=59, 59, 56, 59, 60, 55, 57, 56 | 0.086 Liters | Standard Error 0.023 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 12 h AMD/Pre-PMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.022 Liters | Standard Error 0.023 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 24 h AMD/12 h PMD, n=59, 58, 56, 59, 59, 55, 57,56 | 0.070 Liters | Standard Error 0.024 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 13 h AMD/1 h PMD, n=59, 59, 56, 59, 58, 55, 57, 56 | -0.001 Liters | Standard Error 0.024 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 15 h AMD/3 h PMD, n=59, 58, 56, 58, 59, 55, 57, 56 | -0.008 Liters | Standard Error 0.023 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 23 h AMD/11 h PMD, n=59, 57, 56, 59, 59, 55, 57,56 | 0.006 Liters | Standard Error 0.025 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 1 h AMD, n=59, 59, 56, 59, 60, 55, 57, 56 | 0.112 Liters | Standard Error 0.023 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 3 h AMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.132 Liters | Standard Error 0.024 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 15 h AMD/3 h PMD, n=59, 58, 56, 58, 59, 55, 57, 56 | 0.004 Liters | Standard Error 0.023 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 12 h AMD/Pre-PMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.028 Liters | Standard Error 0.023 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 13 h AMD/1 h PMD, n=59, 59, 56, 59, 58, 55, 57, 56 | -0.003 Liters | Standard Error 0.024 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 23 h AMD/11 h PMD, n=59, 57, 56, 59, 59, 55, 57,56 | -0.006 Liters | Standard Error 0.025 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 24 h AMD/12 h PMD, n=59, 58, 56, 59, 59, 55, 57,56 | 0.065 Liters | Standard Error 0.024 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | Pre-AMD, n=59, 58, 55, 59, 60, 54, 57, 54 | 0.067 Liters | Standard Error 0.021 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 9 h AMD, n=59, 59, 56, 59, 58, 55, 56, 56 | 0.050 Liters | Standard Error 0.022 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 6 h AMD, n=59, 59, 55, 59, 59, 55, 57, 56 | 0.067 Liters | Standard Error 0.022 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | Pre-AMD, n=59, 58, 55, 59, 60, 54, 57, 54 | 0.065 Liters | Standard Error 0.021 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 1 h AMD, n=59, 59, 56, 59, 60, 55, 57, 56 | 0.107 Liters | Standard Error 0.023 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 12 h AMD/Pre-PMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.043 Liters | Standard Error 0.023 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 3 h AMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.082 Liters | Standard Error 0.024 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 6 h AMD, n=59, 59, 55, 59, 59, 55, 57, 56 | 0.056 Liters | Standard Error 0.022 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 9 h AMD, n=59, 59, 56, 59, 58, 55, 56, 56 | 0.084 Liters | Standard Error 0.022 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 13 h AMD/1 h PMD, n=59, 59, 56, 59, 58, 55, 57, 56 | 0.026 Liters | Standard Error 0.024 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 15 h AMD/3 h PMD, n=59, 58, 56, 58, 59, 55, 57, 56 | 0.022 Liters | Standard Error 0.023 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 23 h AMD/11 h PMD, n=59, 57, 56, 59, 59, 55, 57,56 | 0.012 Liters | Standard Error 0.024 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 24 h AMD/12 h PMD, n=59, 58, 56, 59, 59, 55, 57,56 | 0.067 Liters | Standard Error 0.023 |
| UMEC 125 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 1 h AMD, n=59, 59, 56, 59, 60, 55, 57, 56 | 0.167 Liters | Standard Error 0.023 |
| UMEC 125 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 6 h AMD, n=59, 59, 55, 59, 59, 55, 57, 56 | 0.088 Liters | Standard Error 0.022 |
| UMEC 125 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | Pre-AMD, n=59, 58, 55, 59, 60, 54, 57, 54 | 0.122 Liters | Standard Error 0.021 |
| UMEC 125 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 12 h AMD/Pre-PMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.103 Liters | Standard Error 0.023 |
| UMEC 125 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 13 h AMD/1 h PMD, n=59, 59, 56, 59, 58, 55, 57, 56 | 0.103 Liters | Standard Error 0.024 |
| UMEC 125 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 9 h AMD, n=59, 59, 56, 59, 58, 55, 56, 56 | 0.132 Liters | Standard Error 0.022 |
| UMEC 125 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 24 h AMD/12 h PMD, n=59, 58, 56, 59, 59, 55, 57,56 | 0.146 Liters | Standard Error 0.024 |
| UMEC 125 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 15 h AMD/3 h PMD, n=59, 58, 56, 58, 59, 55, 57, 56 | 0.073 Liters | Standard Error 0.023 |
| UMEC 125 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 23 h AMD/11 h PMD, n=59, 57, 56, 59, 59, 55, 57,56 | 0.073 Liters | Standard Error 0.024 |
| UMEC 125 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 3 h AMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.176 Liters | Standard Error 0.024 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | Pre-AMD, n=59, 58, 55, 59, 60, 54, 57, 54 | 0.069 Liters | Standard Error 0.022 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 13 h AMD/1 h PMD, n=59, 59, 56, 59, 58, 55, 57, 56 | 0.063 Liters | Standard Error 0.025 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 23 h AMD/11 h PMD, n=59, 57, 56, 59, 59, 55, 57,56 | 0.001 Liters | Standard Error 0.025 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 1 h AMD, n=59, 59, 56, 59, 60, 55, 57, 56 | 0.128 Liters | Standard Error 0.024 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 3 h AMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.126 Liters | Standard Error 0.025 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 15 h AMD/3 h PMD, n=59, 58, 56, 58, 59, 55, 57, 56 | 0.041 Liters | Standard Error 0.024 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 9 h AMD, n=59, 59, 56, 59, 58, 55, 56, 56 | 0.070 Liters | Standard Error 0.023 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 24 h AMD/12 h PMD, n=59, 58, 56, 59, 59, 55, 57,56 | 0.083 Liters | Standard Error 0.024 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 12 h AMD/Pre-PMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.048 Liters | Standard Error 0.023 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 6 h AMD, n=59, 59, 55, 59, 59, 55, 57, 56 | 0.045 Liters | Standard Error 0.022 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 9 h AMD, n=59, 59, 56, 59, 58, 55, 56, 56 | 0.038 Liters | Standard Error 0.022 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 23 h AMD/11 h PMD, n=59, 57, 56, 59, 59, 55, 57,56 | 0.33 Liters | Standard Error 0.025 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 24 h AMD/12 h PMD, n=59, 58, 56, 59, 59, 55, 57,56 | 0.084 Liters | Standard Error 0.024 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 12 h AMD/Pre-PMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.048 Liters | Standard Error 0.023 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 13 h AMD/1 h PMD, n=59, 59, 56, 59, 58, 55, 57, 56 | 0.041 Liters | Standard Error 0.024 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 1 h AMD, n=59, 59, 56, 59, 60, 55, 57, 56 | 0.135 Liters | Standard Error 0.023 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 3 h AMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.120 Liters | Standard Error 0.024 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 15 h AMD/3 h PMD, n=59, 58, 56, 58, 59, 55, 57, 56 | 0.047 Liters | Standard Error 0.023 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 6 h AMD, n=59, 59, 55, 59, 59, 55, 57, 56 | 0.081 Liters | Standard Error 0.022 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | Pre-AMD, n=59, 58, 55, 59, 60, 54, 57, 54 | 0.097 Liters | Standard Error 0.021 |
| TIO 18 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 23 h AMD/11 h PMD, n=59, 57, 56, 59, 59, 55, 57,56 | 0.002 Liters | Standard Error 0.025 |
| TIO 18 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 13 h AMD/1 h PMD, n=59, 59, 56, 59, 58, 55, 57, 56 | 0.061 Liters | Standard Error 0.025 |
| TIO 18 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 24 h AMD/12 h PMD, n=59, 58, 56, 59, 59, 55, 57,56 | 0.049 Liters | Standard Error 0.024 |
| TIO 18 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 1 h AMD, n=59, 59, 56, 59, 60, 55, 57, 56 | 0.176 Liters | Standard Error 0.023 |
| TIO 18 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 6 h AMD, n=59, 59, 55, 59, 59, 55, 57, 56 | 0.128 Liters | Standard Error 0.022 |
| TIO 18 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | Pre-AMD, n=59, 58, 55, 59, 60, 54, 57, 54 | 0.084 Liters | Standard Error 0.022 |
| TIO 18 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 9 h AMD, n=59, 59, 56, 59, 58, 55, 56, 56 | 0.094 Liters | Standard Error 0.023 |
| TIO 18 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 12 h AMD/Pre-PMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.081 Liters | Standard Error 0.023 |
| TIO 18 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 3 h AMD, n=59, 59, 56, 59, 59, 55, 57, 56 | 0.180 Liters | Standard Error 0.025 |
| TIO 18 µg QD | Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | 15 h AMD/3 h PMD, n=59, 58, 56, 58, 59, 55, 57, 56 | 0.037 Liters | Standard Error 0.023 |
Secondary
Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The weighted mean FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The weighted mean FEV1 was calculated using 0-24 hour post-dose measurements at Day 7 of each treatment period, which included pre-dose and post-dose 1, 3, 6, 9, 12, 13, 15, 23, and 24 hours. Analysis was performed using a mixed model with covariates of mean BL, period BL, treatment, and period as fixed effects and participant as a random effect. BL is the FEV1 value recorded pre-dose on Day 1 of each TP, mean BL is the mean of the BLs for each participant, and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each TP is the weighted mean FEV1 at Day 7 minus the BL value for that TP.
Time frame: Baseline and Day 7 of each treatment period (TP; up to Study Day 49)
Population: mITT Population. All participants with \>=1 post-Baseline assessment and non-missing covariate data are included in the analysis. The number of participants represents participants who provided data at Day 7.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| All Study Treatments | Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period | -0.074 Liters | Standard Error 0.018 |
| UMEC 15.6 µg QD | Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period | 0.043 Liters | Standard Error 0.018 |
| UMEC 31.25 µg QD | Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period | 0.045 Liters | Standard Error 0.019 |
| UMEC 62.5 µg QD | Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period | 0.059 Liters | Standard Error 0.018 |
| UMEC 125 µg QD | Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period | 0.100 Liters | Standard Error 0.018 |
| UMEC 15.6 µg BID | Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period | 0.062 Liters | Standard Error 0.018 |
| UMEC 31.25 µg BID | Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period | 0.068 Liters | Standard Error 0.018 |
| TIO 18 µg QD | Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period | 0.084 Liters | Standard Error 0.018 |