Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
GSK573719, asthma, UMEC, FF, GSK2829332, persistent obstruction, GW685698, Fluticasone Furoate, COPD, umeclidinium bromide
Brief summary
The purpose of this study is to evaluate the dose-response of 4 doses of umeclidinium bromide in combination with fluticasone furoate compared with fluticasone furoate monotherapy in chronic obstructive pulmonary disease participants with an asthmatic component. The fluticasone furoate/umeclidinium bromide treatments will also be compared to the once-daily inhaled corticosteroid/long-acting beta agonist combination fluticasone furoate/vilanterol.
Interventions
DRUGUMEC
Umeclidinium bromide is available as combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister)
DRUGVI
Vilanterol is available as vilanterol inhalation powder (25 mcg per blister) and combination of fluticasone furoate/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, vilanterol: 25 mcg per blister)
DRUGFF
Fluticasone furoate is available as fluticasone furoate inhalation powder (100 mcg per blister), combination of fluticasone furoate/umeclidinium bromide inhalation powder (fluticasone furoate: 100 mcg per blister, umeclidinium bromide: 15.6, 62.5, 125, or 250 mcg per blister) and combination of fluticasone furoate/vilanterol inhalation powder (fluticasone furoate: 100 mcg per blister, vilanterol: 25 mcg per blister)
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years of age or older * COPD with evidence of an asthmatic component as demonstrated by spirometry, reversibility and current therapy at screening as follows: * Post-bronchodilator morning (AM) FEV1 \>=50% and \<=80% of the predicted normal value at Visit 1 * Pre- and post-bronchodilator FEV1/FVC ratio \<0.7. * Demonstrated reversibility by \>=12% and \>=200 mL increase in FEV1 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 12 weeks prior to Visit 1. * Outpatient subjects who are smokers or non-smokers.
Exclusion criteria
* History of life-threatening respiratory event within the last 5 years. * Unresolved respiratory infection * Recent Severe COPD or Asthma Exacerbation * Risk factors for pneumonia * Hospitalization for pneumonia within 3 months * Concurrent respiratory disease other than chronic obstructive pulmonary disease or asthma. * Other uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study. * Viral hepatitis or HIV * Current or chronic history of liver disease, known hepatic or biliary abnormalities * Drug or milk protein allergy * Administration of prescription or over-the-counter medication that would significantly affect the course of COPD or asthma, or interact with study drug * Subjects with lung volume reduction surgery within 12 months prior to screening. * Use of long-term oxygen therapy (LTOT) * Requirement for nebulized therapy * Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks * Unstable or life-threatening cardiac disease * Abnormal and clinically significant 12-Lead Electrocardiogram (ECG) finding * Diseases preventing the use of anticholinergics
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinic Trough Forced Expiratory Volume in One Second (FEV1) at the End of Treatment Phase A (Visit 6/Day 29) | Baseline and Day 29 | FEV1 is defined as forced expiratory volume in one second and measured in the morning at Visits 1 through 8 between 6:00 and 11:00 electronically by spirometry. Change from Baseline in trough FEV1 is defined as the difference in the value obtained at Visit 6 (24 hours post-dose on Visit 5) and the last acceptable/borderline acceptable value obtained prior to randomization (from Visit 2 pre-bronchodilator or Visit 3 pre-dose). Trough FEV1 is defined as the acceptable/borderline acceptable FEV1 value obtained at Visit 6, approximately 24 hours after morning dosing on Visit 5. ITT population is comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period. All comparisons for statistical purposes are with the FF 100 µg arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Rescue Medication Use at the End of Treatment Phase A | Baseline and End of Treatment Phase A (The end of Treatment Phase A was defined as the last 7 days of Treatment Phase A, including the AM assessments on the date of Visit 6) | All participants received the albuterol/salbutamol via MDI as a rescue medication on an as-needed basis. Total daily rescue medication use for a given day is the sum of daytime albuterol/salbutamol use recorded in PM and nighttime albuterol/salbutamol use recorded in AM the next day. The number of puffs of albuterol (salbutamol) MDI used in the last 12 hours for relief of symptoms were recorded morning and evening in the eDiary by the participants. End of Treatment Phase A is the last 7 days of Treatment Phase A. Change from Baseline at the end of Treatment Phase is the difference between the end of Treatment Phase value and the appropriate baseline week. Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline rescue medication use, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. Baseline is the last 7 days of the run-in period prior to randomization |
| Mean Change From Baseline in E-RS Total Scores at the End of Treatment Phase A | Baseline and End of Treatment Phase A (The end of Treatment Phase A was defined as the last 7 days of Treatment Phase A, including the AM assessments on the date of Visit 6) | A daily symptoms score for exacerbations of chronic pulmonary disease tool - Respiratory Symptoms (E-RS) is derived by summing the 11 item-level E-RS scores and has a theoretical range of 0-40, with higher values indicating more severe respiratory symptoms. The Baseline E-RS score is defined as the mean within-subject daily score over the 7 days prior to randomization, with data present for a minimum of 4 of the 7 days. Change from Baseline at the end of Treatment Phase is the difference between the end of Treatment Phase value and the appropriate Baseline week. Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline score, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. Baseline is the last 7 days of the run-in period prior to randomization. All comparisons for statistical purposes are with the FF 100 µg arm. |
| Change From Baseline in Daily Morning (AM) PEF (Pre-dose and Pre-rescue Bronchodilator) Measured at Home and Averaged Over the Last 21 Days of Treatment Phase A | Baseline and from Day 8 through Day 29 | Peak expiratory flow (PEF) stability limit was calculated from AM PEF measurements on the 7 days preceding Visit 3 as mean AM PEF from the available 7 days preceding Visit 3 x 80%. PEF stability limit serves as a benchmark of the participants run-in COPD status and used for comparison during the treatment phase to assess subject safety. Change from Baseline over the last 21 days of Treatment Phase A is the difference between the last 21 days of Treatment Phase A and the appropriate Baseline week. The last 21 days of Treatment Phase A include the AM assessments on the date of Visit 6. AM assessments include the date of Visit 6 and the 20 consecutive days preceding the date of Visit. Analysis performed using analysis of covariance with covariates of treatment, age, sex, Baseline AM PEF, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. Baseline is the last 7 days of the run-in period prior to randomization |
| Change From Trough in Clinic Forced Expiratory Volume (FEV1) at 3 Hours Post-study Treatment at Visit 5/Day 28 | Baseline and Day 28 | FEV1 was measured in the morning by spirometry. At Visit 5, after trough FEV1 is measured, subject received investigational product. 3 hours post-dose, spirometry was repeated and subject then received 2 puffs of albuterol/salbutamol. After 30 minutes,spirometry was repeated.. Change from Baseline in clinic trough (pre-dose) FEV1 is the difference in the trough value at 3 hours post-dose peak FEV1 and the Baseline value. If the trough value or the Baseline was missing, then change from Baseline was considered as missing. Baseline value of clinic FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to randomization (from Visit 3 pre-dose or from Visit 2 pre-bronchodilator). Analysis done using analysis of covariance with covariates of treatment, age, sex, baseline clinic trough FEV1, pre-dose trough FEV1 at Visit 5, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. |
| Change in Clinic FEV1 Following 2 Puffs of Albuterol/Salbutamol Given 3 Hours Post-study Treatment Dose at Visit 5/Day 28 | Baseline and Day 28 | FEV1 is defined as forced expiratory volume in one second and measured in the morning at Visits 1 through 8 between 6:00 and 11:00 electronically by spirometry. Reversibility was measured at Visit 1 and Visit 2 for study eligibility by change in clinic FEV1 within 20 to 60 minutes following 4 inhalations of albuterol/salbutamol and again measured 3 hours after dosing at Visit 5 by change in clinic FEV1 30 minutes following 2 inhalations of albuterol/salbutamol. Baseline value of clinic FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to randomization (either from Visit 3 pre-dose or from Visit 2 pre-bronchodilator). Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline clinic trough FEV1, pre-albuterol/salbutamol FEV1 at Visit 5, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. |
Countries
Argentina, Germany, Poland, Romania, Russia, Ukraine, United States
Participant flow
Recruitment details
Participants (par.) with sufficient signs and symptoms to diagnose as having chronic obstructive pulmonary disease (COPD) and evidence of an asthmatic component as demonstrated by spirometry, reversibility and current therapy at the point of screening were eligible for participation in the study.
Pre-assignment details
Participants on inhaled corticosteroid therapy over the previous 12 weeks, including a stable dose during the 4 weeks prior to Visit 0, entered the 4-week run-in period on open-label fluticasone propionate 250 microgram (µg) and salmeterol 50 µg combination. Eligible par. were stratified by smoking status, age and randomized to Treatment Phase A.
Participants by arm
| Arm | Count |
|---|---|
| FF 100 µg Participants received FF 100 µg once daily in the morning by inhalation using a DPI for 4 weeks in Treatment Phase A. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study. | 41 |
| FF/UMEC 100/15.6 µg Participants received FF 100 µg in combination with UMEC 15.6 µg once daily in the morning by inhalation using a DPI for 4 weeks in Treatment Phase A. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study. | 42 |
| FF/UMEC 100/62.5 µg Participants received FF 100 µg in combination with UMEC 62.5 µg once daily in the morning by inhalation using a DPI for 4 weeks in Treatment Phase A. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study. | 40 |
| FF/UMEC 100/125 µg Participants received FF 100 µg in combination with UMEC 125 µg once daily in the morning by inhalation using a DPI for 4 weeks in Treatment Phase A. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study. | 46 |
| FF/UMEC 100/250 µg Participants received FF 100 µg in combination with UMEC 250 µg once daily in the morning by inhalation using a DPI for 4 weeks in Treatment Phase A. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study. | 85 |
| FF/VI 100/25 µg Participants received FF 100 µg in combination with VI 25 µg once daily in the morning by inhalation using a DPI for 4 weeks in Treatment Phase A. In addition, all participants received supplemental albuterol/salbutamol via MDI to be used on an as-needed basis (rescue medication) throughout the study. | 84 |
| Total | 338 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Treatment Phase A (4 Weeks) | Withdrawal by Subject | 2 | 0 | 1 | 2 | 3 | 1 | 0 |
| Treatment Phase B (1 Week) | Adverse Event | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
| Treatment Phase B (1 Week) | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| Treatment Phase C (1 Week) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Treatment Phase C (1 Week) | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Treatment Phase C (1 Week) | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | FF 100 µg | FF/UMEC 100/15.6 µg | FF/UMEC 100/62.5 µg | FF/UMEC 100/125 µg | FF/UMEC 100/250 µg | FF/VI 100/25 µg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 58.4 Years STANDARD_DEVIATION 8.59 | 55.5 Years STANDARD_DEVIATION 11.33 | 56.7 Years STANDARD_DEVIATION 10.14 | 58.2 Years STANDARD_DEVIATION 10.47 | 57.8 Years STANDARD_DEVIATION 11.03 | 57.6 Years STANDARD_DEVIATION 10.95 | 57.5 Years STANDARD_DEVIATION 10.56 |
| Race/Ethnicity, Customized African American/African Heritage | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 7 Participants |
| Race/Ethnicity, Customized Mixed Race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White- Arabic/ North African Heritage | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White- White/Caucasian/European Heritage | 40 Participants | 42 Participants | 39 Participants | 44 Participants | 81 Participants | 83 Participants | 329 Participants |
| Sex: Female, Male Female | 21 Participants | 23 Participants | 19 Participants | 18 Participants | 38 Participants | 41 Participants | 160 Participants |
| Sex: Female, Male Male | 20 Participants | 19 Participants | 21 Participants | 28 Participants | 47 Participants | 43 Participants | 178 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 | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 111 | 5 / 42 | 4 / 40 | 4 / 46 | 5 / 210 | 4 / 146 | 0 / 163 |
| serious Total, serious adverse events | 0 / 111 | 0 / 42 | 0 / 40 | 0 / 46 | 1 / 210 | 0 / 146 | 0 / 163 |
Outcome results
Primary
Change From Baseline in Clinic Trough Forced Expiratory Volume in One Second (FEV1) at the End of Treatment Phase A (Visit 6/Day 29)
FEV1 is defined as forced expiratory volume in one second and measured in the morning at Visits 1 through 8 between 6:00 and 11:00 electronically by spirometry. Change from Baseline in trough FEV1 is defined as the difference in the value obtained at Visit 6 (24 hours post-dose on Visit 5) and the last acceptable/borderline acceptable value obtained prior to randomization (from Visit 2 pre-bronchodilator or Visit 3 pre-dose). Trough FEV1 is defined as the acceptable/borderline acceptable FEV1 value obtained at Visit 6, approximately 24 hours after morning dosing on Visit 5. ITT population is comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period. All comparisons for statistical purposes are with the FF 100 µg arm.
Time frame: Baseline and Day 29
Population: ITT Population. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg | Change From Baseline in Clinic Trough Forced Expiratory Volume in One Second (FEV1) at the End of Treatment Phase A (Visit 6/Day 29) | 0.047 Liters | Standard Deviation 0.3002 |
| FF/UMEC 100/15.6 µg | Change From Baseline in Clinic Trough Forced Expiratory Volume in One Second (FEV1) at the End of Treatment Phase A (Visit 6/Day 29) | 0.146 Liters | Standard Deviation 0.233 |
| FF/UMEC 100/62.5 µg | Change From Baseline in Clinic Trough Forced Expiratory Volume in One Second (FEV1) at the End of Treatment Phase A (Visit 6/Day 29) | 0.193 Liters | Standard Deviation 0.2192 |
| FF/UMEC 100/125 µg | Change From Baseline in Clinic Trough Forced Expiratory Volume in One Second (FEV1) at the End of Treatment Phase A (Visit 6/Day 29) | 0.175 Liters | Standard Deviation 0.2478 |
| FF/UMEC 100/250 µg | Change From Baseline in Clinic Trough Forced Expiratory Volume in One Second (FEV1) at the End of Treatment Phase A (Visit 6/Day 29) | 0.143 Liters | Standard Deviation 0.315 |
| FF/VI 100/25 µg | Change From Baseline in Clinic Trough Forced Expiratory Volume in One Second (FEV1) at the End of Treatment Phase A (Visit 6/Day 29) | 0.121 Liters | Standard Deviation 0.2779 |
p-value: 0.02495% CI: [0.014, 0.193]Final step dose response model
p-value: 0.02495% CI: [0.014, 0.193]Final step dose response model
p-value: 0.02495% CI: [0.014, 0.193]Final step dose response model
p-value: 0.02495% CI: [0.014, 0.193]Final step dose response model
p-value: 0.15295% CI: [-0.027, 0.172]Final dose response model
Secondary
Change From Baseline in Daily Morning (AM) PEF (Pre-dose and Pre-rescue Bronchodilator) Measured at Home and Averaged Over the Last 21 Days of Treatment Phase A
Peak expiratory flow (PEF) stability limit was calculated from AM PEF measurements on the 7 days preceding Visit 3 as mean AM PEF from the available 7 days preceding Visit 3 x 80%. PEF stability limit serves as a benchmark of the participants run-in COPD status and used for comparison during the treatment phase to assess subject safety. Change from Baseline over the last 21 days of Treatment Phase A is the difference between the last 21 days of Treatment Phase A and the appropriate Baseline week. The last 21 days of Treatment Phase A include the AM assessments on the date of Visit 6. AM assessments include the date of Visit 6 and the 20 consecutive days preceding the date of Visit. Analysis performed using analysis of covariance with covariates of treatment, age, sex, Baseline AM PEF, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. Baseline is the last 7 days of the run-in period prior to randomization
Time frame: Baseline and from Day 8 through Day 29
Population: ITT Population. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg | Change From Baseline in Daily Morning (AM) PEF (Pre-dose and Pre-rescue Bronchodilator) Measured at Home and Averaged Over the Last 21 Days of Treatment Phase A | -14.2 Liters per minute (L/min) | Standard Error 4.62 |
| FF/UMEC 100/15.6 µg | Change From Baseline in Daily Morning (AM) PEF (Pre-dose and Pre-rescue Bronchodilator) Measured at Home and Averaged Over the Last 21 Days of Treatment Phase A | 3.9 Liters per minute (L/min) | Standard Error 4.7 |
| FF/UMEC 100/62.5 µg | Change From Baseline in Daily Morning (AM) PEF (Pre-dose and Pre-rescue Bronchodilator) Measured at Home and Averaged Over the Last 21 Days of Treatment Phase A | 7.6 Liters per minute (L/min) | Standard Error 4.76 |
| FF/UMEC 100/125 µg | Change From Baseline in Daily Morning (AM) PEF (Pre-dose and Pre-rescue Bronchodilator) Measured at Home and Averaged Over the Last 21 Days of Treatment Phase A | 5.5 Liters per minute (L/min) | Standard Error 4.4 |
| FF/UMEC 100/250 µg | Change From Baseline in Daily Morning (AM) PEF (Pre-dose and Pre-rescue Bronchodilator) Measured at Home and Averaged Over the Last 21 Days of Treatment Phase A | 10.5 Liters per minute (L/min) | Standard Error 3.37 |
| FF/VI 100/25 µg | Change From Baseline in Daily Morning (AM) PEF (Pre-dose and Pre-rescue Bronchodilator) Measured at Home and Averaged Over the Last 21 Days of Treatment Phase A | 4.3 Liters per minute (L/min) | Standard Error 3.47 |
p-value: 0.00495% CI: [5.9, 30.3]ANCOVA
p-value: <0.00195% CI: [9.4, 34.1]ANCOVA
p-value: 0.00195% CI: [7.7, 31.7]ANCOVA
p-value: <0.00195% CI: [14.1, 35.4]ANCOVA
p-value: <0.00195% CI: [8, 29.1]ANCOVA
Secondary
Change From Trough in Clinic Forced Expiratory Volume (FEV1) at 3 Hours Post-study Treatment at Visit 5/Day 28
FEV1 was measured in the morning by spirometry. At Visit 5, after trough FEV1 is measured, subject received investigational product. 3 hours post-dose, spirometry was repeated and subject then received 2 puffs of albuterol/salbutamol. After 30 minutes,spirometry was repeated.. Change from Baseline in clinic trough (pre-dose) FEV1 is the difference in the trough value at 3 hours post-dose peak FEV1 and the Baseline value. If the trough value or the Baseline was missing, then change from Baseline was considered as missing. Baseline value of clinic FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to randomization (from Visit 3 pre-dose or from Visit 2 pre-bronchodilator). Analysis done using analysis of covariance with covariates of treatment, age, sex, baseline clinic trough FEV1, pre-dose trough FEV1 at Visit 5, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification.
Time frame: Baseline and Day 28
Population: ITT Population. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg | Change From Trough in Clinic Forced Expiratory Volume (FEV1) at 3 Hours Post-study Treatment at Visit 5/Day 28 | 0.048 Liters (L) | Standard Error 0.0307 |
| FF/UMEC 100/15.6 µg | Change From Trough in Clinic Forced Expiratory Volume (FEV1) at 3 Hours Post-study Treatment at Visit 5/Day 28 | 0.093 Liters (L) | Standard Error 0.0305 |
| FF/UMEC 100/62.5 µg | Change From Trough in Clinic Forced Expiratory Volume (FEV1) at 3 Hours Post-study Treatment at Visit 5/Day 28 | 0.088 Liters (L) | Standard Error 0.0309 |
| FF/UMEC 100/125 µg | Change From Trough in Clinic Forced Expiratory Volume (FEV1) at 3 Hours Post-study Treatment at Visit 5/Day 28 | 0.072 Liters (L) | Standard Error 0.0279 |
| FF/UMEC 100/250 µg | Change From Trough in Clinic Forced Expiratory Volume (FEV1) at 3 Hours Post-study Treatment at Visit 5/Day 28 | 0.052 Liters (L) | Standard Error 0.022 |
| FF/VI 100/25 µg | Change From Trough in Clinic Forced Expiratory Volume (FEV1) at 3 Hours Post-study Treatment at Visit 5/Day 28 | 0.124 Liters (L) | Standard Error 0.0227 |
p-value: 0.26495% CI: [-0.034, 0.125]ANCOVA
p-value: 0.32895% CI: [-0.041, 0.121]ANCOVA
p-value: 0.53495% CI: [-0.054, 0.103]ANCOVA
p-value: 0.89595% CI: [-0.065, 0.075]ANCOVA
p-value: 0.03195% CI: [0.007, 0.146]ANCOVA
Secondary
Change in Clinic FEV1 Following 2 Puffs of Albuterol/Salbutamol Given 3 Hours Post-study Treatment Dose at Visit 5/Day 28
FEV1 is defined as forced expiratory volume in one second and measured in the morning at Visits 1 through 8 between 6:00 and 11:00 electronically by spirometry. Reversibility was measured at Visit 1 and Visit 2 for study eligibility by change in clinic FEV1 within 20 to 60 minutes following 4 inhalations of albuterol/salbutamol and again measured 3 hours after dosing at Visit 5 by change in clinic FEV1 30 minutes following 2 inhalations of albuterol/salbutamol. Baseline value of clinic FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to randomization (either from Visit 3 pre-dose or from Visit 2 pre-bronchodilator). Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline clinic trough FEV1, pre-albuterol/salbutamol FEV1 at Visit 5, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification.
Time frame: Baseline and Day 28
Population: ITT Population. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg | Change in Clinic FEV1 Following 2 Puffs of Albuterol/Salbutamol Given 3 Hours Post-study Treatment Dose at Visit 5/Day 28 | 0.249 Liters (L) | Standard Error 0.0287 |
| FF/UMEC 100/15.6 µg | Change in Clinic FEV1 Following 2 Puffs of Albuterol/Salbutamol Given 3 Hours Post-study Treatment Dose at Visit 5/Day 28 | 0.161 Liters (L) | Standard Error 0.0284 |
| FF/UMEC 100/62.5 µg | Change in Clinic FEV1 Following 2 Puffs of Albuterol/Salbutamol Given 3 Hours Post-study Treatment Dose at Visit 5/Day 28 | 0.159 Liters (L) | Standard Error 0.0284 |
| FF/UMEC 100/125 µg | Change in Clinic FEV1 Following 2 Puffs of Albuterol/Salbutamol Given 3 Hours Post-study Treatment Dose at Visit 5/Day 28 | 0.160 Liters (L) | Standard Error 0.0262 |
| FF/UMEC 100/250 µg | Change in Clinic FEV1 Following 2 Puffs of Albuterol/Salbutamol Given 3 Hours Post-study Treatment Dose at Visit 5/Day 28 | 0.189 Liters (L) | Standard Error 0.0202 |
| FF/VI 100/25 µg | Change in Clinic FEV1 Following 2 Puffs of Albuterol/Salbutamol Given 3 Hours Post-study Treatment Dose at Visit 5/Day 28 | 0.087 Liters (L) | Standard Error 0.0209 |
p-value: 0.01995% CI: [-0.162, -0.014]ANCOVA
p-value: 0.01795% CI: [-0.165, -0.016]ANCOVA
p-value: 0.01795% CI: [-0.162, -0.016]ANCOVA
p-value: 0.06695% CI: [-0.124, 0.004]ANCOVA
p-value: <0.00195% CI: [-0.227, -0.099]ANCOVA
Secondary
Mean Change From Baseline in E-RS Total Scores at the End of Treatment Phase A
A daily symptoms score for exacerbations of chronic pulmonary disease tool - Respiratory Symptoms (E-RS) is derived by summing the 11 item-level E-RS scores and has a theoretical range of 0-40, with higher values indicating more severe respiratory symptoms. The Baseline E-RS score is defined as the mean within-subject daily score over the 7 days prior to randomization, with data present for a minimum of 4 of the 7 days. Change from Baseline at the end of Treatment Phase is the difference between the end of Treatment Phase value and the appropriate Baseline week. Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline score, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. Baseline is the last 7 days of the run-in period prior to randomization. All comparisons for statistical purposes are with the FF 100 µg arm.
Time frame: Baseline and End of Treatment Phase A (The end of Treatment Phase A was defined as the last 7 days of Treatment Phase A, including the AM assessments on the date of Visit 6)
Population: ITT Population. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg | Mean Change From Baseline in E-RS Total Scores at the End of Treatment Phase A | 0.5 Score on scale | Standard Error 0.54 |
| FF/UMEC 100/15.6 µg | Mean Change From Baseline in E-RS Total Scores at the End of Treatment Phase A | -2.6 Score on scale | Standard Error 0.55 |
| FF/UMEC 100/62.5 µg | Mean Change From Baseline in E-RS Total Scores at the End of Treatment Phase A | -2.5 Score on scale | Standard Error 0.56 |
| FF/UMEC 100/125 µg | Mean Change From Baseline in E-RS Total Scores at the End of Treatment Phase A | -1.5 Score on scale | Standard Error 0.52 |
| FF/UMEC 100/250 µg | Mean Change From Baseline in E-RS Total Scores at the End of Treatment Phase A | -1.5 Score on scale | Standard Error 0.4 |
| FF/VI 100/25 µg | Mean Change From Baseline in E-RS Total Scores at the End of Treatment Phase A | -1.1 Score on scale | Standard Error 0.41 |
p-value: <0.00195% CI: [-4.6, -1.7]ANCOVA
p-value: <0.00195% CI: [-4.5, -1.6]ANCOVA
p-value: 0.00795% CI: [-3.4, -0.6]ANCOVA
p-value: 0.00295% CI: [-3.2, -0.7]ANCOVA
p-value: 0.00995% CI: [-2.9, -0.4]ANCOVA
Secondary
Mean Change From Baseline in Rescue Medication Use at the End of Treatment Phase A
All participants received the albuterol/salbutamol via MDI as a rescue medication on an as-needed basis. Total daily rescue medication use for a given day is the sum of daytime albuterol/salbutamol use recorded in PM and nighttime albuterol/salbutamol use recorded in AM the next day. The number of puffs of albuterol (salbutamol) MDI used in the last 12 hours for relief of symptoms were recorded morning and evening in the eDiary by the participants. End of Treatment Phase A is the last 7 days of Treatment Phase A. Change from Baseline at the end of Treatment Phase is the difference between the end of Treatment Phase value and the appropriate baseline week. Analysis performed using analysis of covariance with covariates of treatment, age, sex, baseline rescue medication use, pack years smoked per randomization stratification and age when first treated with an inhaler per randomization stratification. Baseline is the last 7 days of the run-in period prior to randomization
Time frame: Baseline and End of Treatment Phase A (The end of Treatment Phase A was defined as the last 7 days of Treatment Phase A, including the AM assessments on the date of Visit 6)
Population: ITT Population. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg | Mean Change From Baseline in Rescue Medication Use at the End of Treatment Phase A | 0.6 Puffs | Standard Error 0.29 |
| FF/UMEC 100/15.6 µg | Mean Change From Baseline in Rescue Medication Use at the End of Treatment Phase A | -0.4 Puffs | Standard Error 0.29 |
| FF/UMEC 100/62.5 µg | Mean Change From Baseline in Rescue Medication Use at the End of Treatment Phase A | -0.5 Puffs | Standard Error 0.29 |
| FF/UMEC 100/125 µg | Mean Change From Baseline in Rescue Medication Use at the End of Treatment Phase A | 0.0 Puffs | Standard Error 0.27 |
| FF/UMEC 100/250 µg | Mean Change From Baseline in Rescue Medication Use at the End of Treatment Phase A | -0.2 Puffs | Standard Error 0.21 |
| FF/VI 100/25 µg | Mean Change From Baseline in Rescue Medication Use at the End of Treatment Phase A | -0.1 Puffs | Standard Error 0.21 |
p-value: 0.0195% CI: [-1.7, -0.2]ANCOVA
p-value: 0.00495% CI: [-1.9, -0.4]ANCOVA
p-value: 0.08395% CI: [-1.4, 0.1]ANCOVA
p-value: 0.01495% CI: [-1.5, -0.2]ANCOVA
p-value: 0.03195% CI: [-1.4, -0.1]ANCOVA