Asthma
Conditions
Keywords
Fluticasone Furoate, Vilanterol, Adults, GSK573719, Asthma
Brief summary
Brief Summary: The purpose of this study is to characterize the dose response of GSK573719 in combination with Fluticasone furoate 100mcg in patients with asthma. Treatment with inhaled Fluticasone furoate and Fluticasone furoate/Vilanterol are included as an active control. Detailed Description: Long acting muscarinic receptor antagonists (anti-cholinergic bronhcodilator) exert their effects via distinct and complementary bronchodilator mechanisms on large and small airways. Most of the experience with older anti-cholinergics had been with acute use and little is known about their effect in chronic use in asthma. This is a multicenter, randomized, double-blind, crossover study to evaluate 5 doses of inhaled GSK573719 inhaled over 14 days in patients with asthma. Fluticasone furoate (100 mcg) and Fluticasone furoate/Vilanterol (100/59mcg) will be included as an active comparator. Each eligible subject will receive a sequence of 3 of 7 potential treatments for a total of 3 treatment periods per subject. The total duration of subject participation is approximately 14 weeks.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Outpatient * 18 years of age or older at Visit 1 * Diagnosis of Asthma * Male or eligible Female * Pre-bronchodilator FEV1 of 40-80% of the predicted normal value at Visit 1 * Demonstrated reversibility by ≥12% and ≥200mL of FEV1 within 40 minutes following albuterol at Visit 1 * A need for regular controller therapy (i.e., inhaled corticosteroids alone or in combination with a long-acting beta-agonist, or leukotriene modifier etc.,) for a minimum of 8 weeks prior to Visit 1.
Exclusion criteria
* History of Life threatening asthma * Respiratory infection not resolved * Asthma exacerbation * Concurrent respiratory disease * Current Smokers * Other diseases that are uncontrolled disease or disease state that, in the opinion of the investigator, would put the safety of the patient at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study * A positive Hepatitis B surface antigen or positive Hepatitis C antibody and/or HIV * Visual clinical evidence of oropharyngeal candidiasis * Drug or milk protein allergies * Concomitant medications affecting course of asthma * Use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer) * Previous use of GSK573719 * Any disease preventing use of anticholinergics * Any condition that impairs compliance with study protocol including visit schedule and completion of daily diaries * Any subject with a history of alcohol or substance abuse * Any affiliation with Investigator's site
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Model Predicted Change From Baseline Trough Force Expiratory Volume in 1 Second (FEV1) | Baseline (Day 1) and Day 15 of each treatment period | FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. Highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 ante meridiem (AM) and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. Change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Slope-intercept on log dose model was used to predict trough FEV1 change from baseline for each of the FF+UMEC doses adjusted by FF 100 mcg alone. Mean value for the expected response and associated 95% confidence interval (CI) in change from baseline trough FEV1 is presented. |
| Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Baseline (Day 1) and Day 15 of each treatment period | FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. Highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 AM and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. Change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Data is presented as percentage chance that FF 100 mcg alone corrected change from baseline trough FEV1 response would exceed a target response of 50 mL, 75 mL, 100 mL and 150 mL by doses of UMEC combined with FF 100 mcg. |
| Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods | Baseline (Day 1) and Day 15 of each treatment period | FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. The highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 AM and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as the FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. The change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Analysis was done using a mixed model, including treatment, period, period baseline FEV1, and mean baseline FEV1 as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period | Baseline (Week 0) and last 7 days of each treatment period | PEF is a measure of lung function and measures how fast a person can breathe out. Morning PEF was measured pre-dose and pre- rescue bronchodilator use with an electronic Peak Flow Meter. Participants were issued an electronic diary (eDiary) for daily use throughout the study and instructed on how to complete it. Best of 3 attempts were recorded in eDiary. Mean change from baseline was calculated where, baseline was defined as the measurement from (Week 0), includes Day 1 and six days immediately preceding Day 1 for each treatment period. The change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and baseline week. Analysis was done using a mixed model, including treatment, period, period baseline morning PEF and mean baseline morning PEF as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC. |
| Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period | Baseline (Week 0) and last 7 days of each treatment period | PEF is a measure of lung function and measures how fast a person can breathe out. Evening PEF was measured pre-dose and pre-rescue bronchodilator use with an electronic Peak Flow Meter. Participants were issued an electronic diary (eDiary) for daily use throughout the study and instructed on how to complete it. Best of 3 attempts were recorded in eDiary. Mean change from baseline was calculated where, baseline was defined as the measurement from (Week 0), includes Day 1 and seven days immediately preceding Day 1 for each treatment period. The change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and baseline week. Analysis was done using a mixed model, including treatment, period, period baseline evening PEF and mean baseline evening PEF as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC. |
| Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period. | Baseline (Week 0) and last 7 days of each treatment period | Short-Acting Beta2-Agonists albuterol/salbutamol was provided to participants as rescue medication, to use in morning and evening. Participants recorded number of puffs of salbutamol MDI used in last 24 hours (sum of night time and day time puffs) daily for relief of symptoms in eDiary. Mean change from baseline was calculated where, baseline was defined as measurement from (Week 0), includes Day 1 and six days immediately preceding Day 1 (for night time puffs) and seven days (for day time puffs) for each treatment period. Change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and the baseline week. Analysis was done using a mixed model, including treatment, period, period baseline rescue albuterol use, and mean baseline rescue albuterol use as fixed effects and participant as random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC. |
Countries
Argentina, Chile, Russia, Thailand, United States
Participant flow
Recruitment details
The study was conducted across 33 centres of 5 countries from 03 April 2012 to 04 February 2013 in adults aged 18 to 50 years with persistent asthma. Participants were randomized for 3 treatment periods of 2 weeks each.
Pre-assignment details
A total of 706 participants were screened for this study designed in 3 period crossover, incomplete block manner; 523 participants entered 2-week open label run-in period where they received fluticasone furoate (FF) 100 micrograms (mcg) dry powder inhalation once daily. A total of 421 participants were randomized to double-blind treatment period.
Participants by arm
| Arm | Count |
|---|---|
| All Treatments Combined The participants received 3 of the 7 possible treatments during the 3 double blind treatment periods. Participants received study treatments in a crossover manner according to their randomization sequence. The 7 treatment regimens were, FF 100 mcg, FF 100 mcg + UMEC 15.6 mcg, FF 100 mcg + UMEC 31.25 mcg, FF 100 mcg + UMEC 62.5 mcg, FF 100 mcg + UMEC 125 mcg, FF 100 mcg + UMEC 250 mcg and FF 100 mcg + VI 25 mcg. The study treatments were administered via a DPI taken once daily in the morning for 14 days during each study period. The treatment periods were separated by 2 washout periods of 12-14 days each. During the two week run-in period and during the two washout period, participants were administered open-label FF 100 mcg once daily in the morning via a DPI. Participants were followed-up for 7 days post-treatment. Salbutamol MDI was provided as the rescue medication. | 421 |
| Total | 421 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Period 1 : Treatment Period 1 (14 Days) | Adverse Event | 0 | 0 | 1 | 0 | 0 | 1 | 0 |
| Period 1 : Treatment Period 1 (14 Days) | Lack of Efficacy | 4 | 3 | 6 | 1 | 2 | 0 | 1 |
| Period 1 : Treatment Period 1 (14 Days) | Protocol-defined stopping criteria | 0 | 0 | 1 | 1 | 0 | 1 | 1 |
| Period 1 : Treatment Period 1 (14 Days) | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 1 : Treatment Period 1 (14 Days) | Withdrawal by Subject | 1 | 0 | 1 | 0 | 0 | 2 | 0 |
| Period 2 : Washout Period 1 (12-14 Days) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Period 2 : Washout Period 1 (12-14 Days) | Lack of Efficacy | 0 | 1 | 0 | 1 | 0 | 0 | 1 |
| Period 2 : Washout Period 1 (12-14 Days) | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Period 2 : Washout Period 1 (12-14 Days) | Protocol-defined stopping criteria | 0 | 0 | 1 | 1 | 0 | 1 | 0 |
| Period 2 : Washout Period 1 (12-14 Days) | Protocol Violation | 1 | 0 | 2 | 1 | 0 | 0 | 0 |
| Period 2 : Washout Period 1 (12-14 Days) | Withdrawal by Subject | 0 | 0 | 0 | 2 | 0 | 0 | 1 |
| Period 3 : Treatment Period 2 (14 Days) | Lack of Efficacy | 5 | 4 | 2 | 1 | 3 | 2 | 0 |
| Period 3 : Treatment Period 2 (14 Days) | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 3 : Treatment Period 2 (14 Days) | Protocol-defined stopping criteria | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 3 : Treatment Period 2 (14 Days) | Protocol Violation | 0 | 1 | 0 | 0 | 0 | 2 | 0 |
| Period 3 : Treatment Period 2 (14 Days) | Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 | 1 | 0 |
| Period 4 : Washout Period 2 (12-14 Days) | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| Period 4 : Washout Period 2 (12-14 Days) | Lack of Efficacy | 0 | 1 | 1 | 1 | 1 | 0 | 1 |
| Period 4 : Washout Period 2 (12-14 Days) | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Period 4 : Washout Period 2 (12-14 Days) | Protocol-defined stopping criteria | 0 | 1 | 1 | 1 | 0 | 1 | 0 |
| Period 4 : Washout Period 2 (12-14 Days) | Protocol Violation | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Period 4 : Washout Period 2 (12-14 Days) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Period 5 : Treatment Period 3 (14 Days) | Lack of Efficacy | 2 | 0 | 0 | 0 | 1 | 1 | 4 |
| Period 5 : Treatment Period 3 (14 Days) | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 5 : Treatment Period 3 (14 Days) | Protocol Violation | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
| Period 6 : Follow-up Period (7 Days) | Adverse Event | 0 | 0 | 0 | 0 | 2 | 1 | 0 |
| Period 6 : Follow-up Period (7 Days) | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | All Treatments Combined |
|---|---|
| Age, Continuous | 47.5 Years STANDARD_DEVIATION 13.84 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 36 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 367 Participants |
| Sex: Female, Male Female | 289 Participants |
| Sex: Female, Male Male | 132 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 187 | 0 / 183 | 0 / 179 | 0 / 180 | 0 / 176 | 0 / 186 | 0 / 172 |
| other Total, other adverse events | 3 / 187 | 4 / 183 | 2 / 179 | 5 / 180 | 4 / 176 | 7 / 186 | 6 / 172 |
| serious Total, serious adverse events | 0 / 187 | 0 / 183 | 1 / 179 | 0 / 180 | 0 / 176 | 0 / 186 | 1 / 172 |
Outcome results
Primary
Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods
FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. The highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 AM and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as the FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. The change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Analysis was done using a mixed model, including treatment, period, period baseline FEV1, and mean baseline FEV1 as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.
Time frame: Baseline (Day 1) and Day 15 of each treatment period
Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 mcg + UMEC 15.6 mcg | Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods | 0.120 Litres (L) | Standard Error 0.0175 |
| FF 100 mcg + UMEC 31.25 mcg | Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods | 0.145 Litres (L) | Standard Error 0.017 |
| FF 100 mcg + UMEC 62.5 mcg | Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods | 0.152 Litres (L) | Standard Error 0.0174 |
| FF 100 mcg + UMEC 125 mcg | Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods | 0.145 Litres (L) | Standard Error 0.0172 |
| FF 100 mcg + UMEC 250 mcg | Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods | 0.174 Litres (L) | Standard Error 0.017 |
| FF 100 mcg + UMEC 250 mcg | Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods | 0.175 Litres (L) | Standard Error 0.0172 |
| FF 100 mcg + VI 25 mcg | Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods | 0.198 Litres (L) | Standard Error 0.0174 |
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: 0.26495% CI: [-0.019, 0.071]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: 0.16595% CI: [-0.013, 0.079]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: 0.27195% CI: [-0.02, 0.071]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: 0.01895% CI: [0.01, 0.1]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: 0.01895% CI: [0.01, 0.101]Mixed Models Analysis
p-value: <0.00195% CI: [0.032, 0.124]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.02395% CI: [-0.097, -0.007]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.05195% CI: [-0.091, 0]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.02395% CI: [-0.098, -0.007]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.30695% CI: [-0.068, 0.021]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.3395% CI: [-0.068, 0.023]Mixed Models Analysis
Primary
Model Predicted Change From Baseline Trough Force Expiratory Volume in 1 Second (FEV1)
FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. Highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 ante meridiem (AM) and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. Change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Slope-intercept on log dose model was used to predict trough FEV1 change from baseline for each of the FF+UMEC doses adjusted by FF 100 mcg alone. Mean value for the expected response and associated 95% confidence interval (CI) in change from baseline trough FEV1 is presented.
Time frame: Baseline (Day 1) and Day 15 of each treatment period
Population: The primary endpoint was analyzed using Intent -to -Treat (ITT) Population defined as all participants randomized to treatment and who received at least one dose of study medication. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| FF 100 mcg + UMEC 15.6 mcg | Model Predicted Change From Baseline Trough Force Expiratory Volume in 1 Second (FEV1) | 0.0260 Litres (L) |
| FF 100 mcg + UMEC 31.25 mcg | Model Predicted Change From Baseline Trough Force Expiratory Volume in 1 Second (FEV1) | 0.0320 Litres (L) |
| FF 100 mcg + UMEC 62.5 mcg | Model Predicted Change From Baseline Trough Force Expiratory Volume in 1 Second (FEV1) | 0.0385 Litres (L) |
| FF 100 mcg + UMEC 125 mcg | Model Predicted Change From Baseline Trough Force Expiratory Volume in 1 Second (FEV1) | 0.0444 Litres (L) |
| FF 100 mcg + UMEC 250 mcg | Model Predicted Change From Baseline Trough Force Expiratory Volume in 1 Second (FEV1) | 0.0510 Litres (L) |
Primary
Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg
FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. Highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 AM and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. Change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Data is presented as percentage chance that FF 100 mcg alone corrected change from baseline trough FEV1 response would exceed a target response of 50 mL, 75 mL, 100 mL and 150 mL by doses of UMEC combined with FF 100 mcg.
Time frame: Baseline (Day 1) and Day 15 of each treatment period
Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FF 100 mcg + UMEC 15.6 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 50 mL | 9 Percentage chance |
| FF 100 mcg + UMEC 15.6 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 75 mL | 0.5 Percentage chance |
| FF 100 mcg + UMEC 15.6 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 100 mL | 0 Percentage chance |
| FF 100 mcg + UMEC 15.6 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 150 mL | 0 Percentage chance |
| FF 100 mcg + UMEC 31.25 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 50 mL | 17 Percentage chance |
| FF 100 mcg + UMEC 31.25 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 150 mL | 0 Percentage chance |
| FF 100 mcg + UMEC 31.25 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 75 mL | 1 Percentage chance |
| FF 100 mcg + UMEC 31.25 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 100 mL | 0 Percentage chance |
| FF 100 mcg + UMEC 62.5 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 150 mL | 0 Percentage chance |
| FF 100 mcg + UMEC 62.5 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 75 mL | 2 Percentage chance |
| FF 100 mcg + UMEC 62.5 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 100 mL | 0 Percentage chance |
| FF 100 mcg + UMEC 62.5 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 50 mL | 27 Percentage chance |
| FF 100 mcg + UMEC 125 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 50 mL | 37 Percentage chance |
| FF 100 mcg + UMEC 125 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 75 mL | 5 Percentage chance |
| FF 100 mcg + UMEC 125 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 150 mL | 0 Percentage chance |
| FF 100 mcg + UMEC 125 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 100 mL | 0.2 Percentage chance |
| FF 100 mcg + UMEC 250 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 150 mL | 0 Percentage chance |
| FF 100 mcg + UMEC 250 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 100 mL | 0.2 Percentage chance |
| FF 100 mcg + UMEC 250 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 75 mL | 10 Percentage chance |
| FF 100 mcg + UMEC 250 mcg | Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | Target response of 50 mL | 52 Percentage chance |
Secondary
Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period
PEF is a measure of lung function and measures how fast a person can breathe out. Evening PEF was measured pre-dose and pre-rescue bronchodilator use with an electronic Peak Flow Meter. Participants were issued an electronic diary (eDiary) for daily use throughout the study and instructed on how to complete it. Best of 3 attempts were recorded in eDiary. Mean change from baseline was calculated where, baseline was defined as the measurement from (Week 0), includes Day 1 and seven days immediately preceding Day 1 for each treatment period. The change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and baseline week. Analysis was done using a mixed model, including treatment, period, period baseline evening PEF and mean baseline evening PEF as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.
Time frame: Baseline (Week 0) and last 7 days of each treatment period
Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 mcg + UMEC 15.6 mcg | Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period | -5.2 L/min | Standard Error 2.51 |
| FF 100 mcg + UMEC 31.25 mcg | Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period | 11.1 L/min | Standard Error 2.53 |
| FF 100 mcg + UMEC 62.5 mcg | Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period | 12.1 L/min | Standard Error 2.54 |
| FF 100 mcg + UMEC 125 mcg | Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period | 16.0 L/min | Standard Error 2.56 |
| FF 100 mcg + UMEC 250 mcg | Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period | 23.7 L/min | Standard Error 2.52 |
| FF 100 mcg + UMEC 250 mcg | Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period | 17.7 L/min | Standard Error 2.52 |
| FF 100 mcg + VI 25 mcg | Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period | 21.4 L/min | Standard Error 2.58 |
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: <0.00195% CI: [9.5, 22.9]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: <0.00195% CI: [10.5, 24]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: <0.00195% CI: [14.4, 28]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: <0.00195% CI: [22.1, 35.5]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: <0.00195% CI: [16.2, 29.6]Mixed Models Analysis
p-value: <0.00195% CI: [19.8, 33.4]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.00395% CI: [-17.2, -3.5]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.00795% CI: [-16.2, -2.5]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.12695% CI: [-12.3, 1.5]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.52395% CI: [-4.6, 9.1]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.2995% CI: [-10.5, 3.1]Mixed Models Analysis
Secondary
Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period
PEF is a measure of lung function and measures how fast a person can breathe out. Morning PEF was measured pre-dose and pre- rescue bronchodilator use with an electronic Peak Flow Meter. Participants were issued an electronic diary (eDiary) for daily use throughout the study and instructed on how to complete it. Best of 3 attempts were recorded in eDiary. Mean change from baseline was calculated where, baseline was defined as the measurement from (Week 0), includes Day 1 and six days immediately preceding Day 1 for each treatment period. The change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and baseline week. Analysis was done using a mixed model, including treatment, period, period baseline morning PEF and mean baseline morning PEF as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.
Time frame: Baseline (Week 0) and last 7 days of each treatment period
Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 mcg + UMEC 15.6 mcg | Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period | -2.9 Litres per min (L/min) | Standard Error 2.44 |
| FF 100 mcg + UMEC 31.25 mcg | Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period | 13.0 Litres per min (L/min) | Standard Error 2.44 |
| FF 100 mcg + UMEC 62.5 mcg | Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period | 14.5 Litres per min (L/min) | Standard Error 2.46 |
| FF 100 mcg + UMEC 125 mcg | Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period | 15.7 Litres per min (L/min) | Standard Error 2.47 |
| FF 100 mcg + UMEC 250 mcg | Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period | 20.0 Litres per min (L/min) | Standard Error 2.44 |
| FF 100 mcg + UMEC 250 mcg | Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period | 19.0 Litres per min (L/min) | Standard Error 2.44 |
| FF 100 mcg + VI 25 mcg | Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period | 24.1 Litres per min (L/min) | Standard Error 2.46 |
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: <0.00195% CI: [9.5, 22.3]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: <0.00195% CI: [10.9, 23.9]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: <0.00195% CI: [12.1, 25.1]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: <0.00195% CI: [16.5, 29.4]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: <0.00195% CI: [15.5, 28.4]Mixed Models Analysis
p-value: <0.00195% CI: [20.6, 33.5]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: <0.00195% CI: [-17.6, -4.7]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.00495% CI: [-16.1, -3.1]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.01295% CI: [-14.9, -1.9]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.20995% CI: [-10.6, 2.3]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.12495% CI: [-11.6, 1.4]Mixed Models Analysis
Secondary
Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period.
Short-Acting Beta2-Agonists albuterol/salbutamol was provided to participants as rescue medication, to use in morning and evening. Participants recorded number of puffs of salbutamol MDI used in last 24 hours (sum of night time and day time puffs) daily for relief of symptoms in eDiary. Mean change from baseline was calculated where, baseline was defined as measurement from (Week 0), includes Day 1 and six days immediately preceding Day 1 (for night time puffs) and seven days (for day time puffs) for each treatment period. Change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and the baseline week. Analysis was done using a mixed model, including treatment, period, period baseline rescue albuterol use, and mean baseline rescue albuterol use as fixed effects and participant as random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC.
Time frame: Baseline (Week 0) and last 7 days of each treatment period
Population: ITT Population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 mcg + UMEC 15.6 mcg | Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period. | -0.2 Number of puffs | Standard Error 0.09 |
| FF 100 mcg + UMEC 31.25 mcg | Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period. | -0.4 Number of puffs | Standard Error 0.09 |
| FF 100 mcg + UMEC 62.5 mcg | Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period. | -0.4 Number of puffs | Standard Error 0.09 |
| FF 100 mcg + UMEC 125 mcg | Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period. | -0.3 Number of puffs | Standard Error 0.09 |
| FF 100 mcg + UMEC 250 mcg | Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period. | -0.5 Number of puffs | Standard Error 0.09 |
| FF 100 mcg + UMEC 250 mcg | Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period. | -0.4 Number of puffs | Standard Error 0.09 |
| FF 100 mcg + VI 25 mcg | Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period. | -0.6 Number of puffs | Standard Error 0.09 |
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: 0.03695% CI: [-0.5, 0]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: 0.06495% CI: [-0.5, 0]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: 0.33595% CI: [-0.3, 0.1]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: 0.01295% CI: [-0.5, -0.1]Mixed Models Analysis
Comparison: No pairwise comparisons between doses of FF + UMEC and FF alone were done unless overall F-test for treatment effect was statistically significant at 5% level. Multiplicity across these comparisons was controlled using a step-down closed testing procedure, whereby statistical comparison of the highest dose of FF + UMEC and FF alone was initially performed, and subsequent comparisons at lower doses continued in a step-down manner if preceding comparison was statistically significant at 5% level.p-value: 0.02395% CI: [-0.5, 0]Mixed Models Analysis
p-value: <0.00195% CI: [-0.7, -0.2]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.10495% CI: [0, 0.4]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.06295% CI: [0, 0.5]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.00695% CI: [0.1, 0.6]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.21795% CI: [-0.1, 0.4]Mixed Models Analysis
Comparison: No adjustments were made for comparisons between doses of FF + UMEC and FF + VI.p-value: 0.14395% CI: [-0.1, 0.4]Mixed Models Analysis