Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
anticholinergic, long-acting beta agonist
Brief summary
This is a phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GSK573719/GW642444 Inhalation Powder, GSK573719 Inhalation Powder, GW642444 Inhalation Powder and Placebo when administered once-daily via a Novel Dry Powder Inhaler over a 24-week treatment period in subjects with COPD. Subjects who meet eligibility criteria at Screening (Visit 1) will complete a 7 to14 day run-in period followed by a randomization visit (Visit 2) then a 24-week treatment period. There will be a total of 9 clinic study visits. A follow-up phone contact for adverse event assessment will be conducted approximately one week after the last study visit (Visit 9 or Early Withdrawal). The total duration of subject participation in the study will be approximately 27 weeks. A subset of subjects at selected sites will also perform 24-hour serial spirometry and Holter monitoring during the study and provide serial blood samples for pharmacokinetic analysis. Sparse pharmacokinetic sampling for population pharmacokinetic analyses will be obtained from non-subset subjects. The primary measure of efficacy is clinic visit trough (pre-bronchodilator and pre-dose) FEV1 on Treatment Day 169. Safety will be assessed by adverse events, 12-lead ECGs, vital signs, clinical laboratory tests, and 24 hour Holter monitoring (subset only).
Detailed description
This is a 24-week, phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eligible subjects will be randomized to GSK573719/GW642444 125/25mcg, GSK573719 125mcg, GW642444 25mcg, and placebo treatment groups in a 3:3:3:2 ratio such that of the planned 1463 total number of randomized subjects approximately 399 subjects will be randomized to each active treatment group and 266 subjects will be randomized to placebo. All treatments will be administered once-daily in the morning by inhalation using a Novel Dry Powder Inhaler (Novel DPI). There will be a total of 9 study clinic visits conducted on an outpatient basis. Subjects who meet the eligibility criteria at Screening (Visit 1) will complete a 7 to 14 day run-in period followed by a 24-week treatment period. Clinic visits will be at Screening, Randomization (Day 1), Day 2, after 4, 8, 12, 16, and 24-weeks of treatment, and 1 day after the Week 24 Visit (also referred as Treatment Day 169). A follow-up contact for adverse assessment will be conducted by telephone approximately 7 days after Visit 9 or the Early Withdrawal Visit. The total duration of subject participation, including follow-up will be approximately 27 weeks. All subjects will be provided with albuterol/salbutamol for use on an as-needed basis throughout the run-in and study treatment periods. At screening, pre-bronchodilator spirometry testing will be followed by post-albuterol/salbutamol spirometry testing. Post-albuterol/salbutamol FEV1 and FEV1/FVC values will be used to determine subject eligibility. To further characterize bronchodilator responsiveness, post-ipratropium testing will be conducted following completion of post-albuterol/salbutamol spirometry. Spirometry will be conducted at each post-randomization clinic visit. Six hour post-dose serial spirometry will be conducted at Visits 2, 4, 6, and 8. Trough spirometry will be obtained 23 and 24 hours after the previous day's dose of blinded study medication at Visits 3 to 9. All subjects will be provided with an electronic diary (eDiary) for completion daily in the evening throughout the run-in and treatment periods. Subjects will use the eDiary to record dyspnea scores using the Shortness of Breath with Daily Activities instrument (SOBDA), daily use of supplemental albuterol/salbutamol as either puffs/day from a metered-dose inhaler (MDI) and/or nebules used per day, and any healthcare contacts related to COPD. Additional assessments of dyspnea will be obtained using the Baseline and Transition Dyspnea Index (BDI/TDI) which is an interviewer based instrument. At Visit 2, the severity of dyspnea at baseline will be assessed using the BDI. At subsequent visits (Visits 4, 6, and 8) change from baseline will be assessed using the TDI. Disease specific health status will be evaluated using the subject-completed St. George's Respiratory Questionnaire (SGRQ). The SGRQ will be completed at Visits 2, 4, 6, and 8. Administration of the SGRQ and BDI/TDI should be done prior to spirometry testing. The occurrence of adverse events will be evaluated throughout the study beginning at Visit 2. SAEs will be collected over the same time period as for AEs. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be recorded from the time a subject consents to participate in the study up to and including any follow up contact. Additional safety assessments of vital signs (blood pressure and pulse rate), 12-lead ECGs and standard clinical laboratory tests (hematology and chemistry) will be obtained at selected clinic visits. Blood samples for population pharmacokinetic analyses will be obtained. At selected study sites, a subset of approximately 198 subjects will perform 24-hour serial spirometry during the study for evaluation of lung function over the dosing period. In conjunction with the serial spirometry, this subset of subjects will also perform 24 hour Holter monitoring and provide blood samples for PK analysis.
Interventions
DRUGGSK573719/GW642444 125/25mcg
125/25mcg
DRUGGSK573719 125mcg
125mcg
DRUGGW642444 25mcg
25mcg
DRUGPlacebo only
Placebo
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of COPD * 10 pack-year or greater history of cigarette smoking * Post-bronchodilator FEV1/FVC of \<0.7 * Predicted FEV1 of 70% of normal or less * Modified Medical Research Council (mMRC) dyspnea score of 2 or greater
Exclusion criteria
* Women who are pregnant, lactating, or planning to become pregnant * Respiratory disorders other than COPD, including a current diagnosis of asthma * Clinically significant non-respiratory diseases or abnormalities that are not adequately controlled * Significant allergy or hypersensitivity to anticholinergics, beta2-agonists, or the excipients of magnesium stereate or lactose used in the inhaler delivery device * Hospitalization for COPD or pneumonia within 12 weeks prior to screening * Lung volume reduction surgery within 12 weeks prior to screening * Abnormal and clinically significant ECG findings at screening * Clinically significant laboratory findings at screening * Use of systemic corticosteroids, antibiotics for respiratory tract infections, strong cytochrome P450 3A4 inhibitors, high dose inhaled steroids (\>1000mcg fluticasone propionate or equivalent), PDE4 inhibitors, tiotropium, oral beta2-agoinists, short- and long-acting inhaled beta2-agonists, ipratropium, inhaled sodium cromoglycate or nedocromil sodium, or investigational medicines for defined time periods prior to the screening visit * Use of long-term oxygen therapy (12 hours or greater per day) * Regular use of nebulized treatment with short-acting bronchodilators * Participation in the acute phase of a pulmonary rehabilitation program * A know or suspected history of alcohol or drug abuse * Affiliation with the investigational site * Previous use of GSK573719 or GW642444 alone or in combination, including the combination of fluticasone furoate and GW642444
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24) | Baseline and Day 169 | 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 measurements were taken electronically by spirometry on Days 2, 28, 56, 84, 112, 168, and 169. Baseline is defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Trough FEV1 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous morning's dosing (ie., trough FEV1 on Day 169 is the mean of the FEV1 values obtained 23 and 24 hours after the morning dosing on Day 168). Change from Baseline at a particular visit was calculated as the trough FEV1 at that visit minus Baseline. Analysis was performed using a repeated measures model with covariates of treatment, Baseline , smoking status, center group, day, and day by Baseline and day by treatment interactions. ITT=Intent-to-Treat; par.=participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Transition Dyspnea Index (TDI) Focal Score at Day 168 (Week 24) | Day 168 (Week 24) | Considered an 'other' endpoint by the FDA. The TDI is an interviewer-administered instrument which measures the changes in the participant's dyspnea from Baseline. This questionnaire was collected on Days 28, 84 and 168. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9. Analysis was performed using a repeated measures model with covariates of treatment, Baseline dyspnea index (BDI) focal score,smoking status, center group, day, day by BDI focal score and day by treatment interactions. |
| Change From Baseline in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168 | Baseline and Day 168 | 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 WM 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 WM was calculated at Days 1, 28, 84, and 168 using the 0-6-hour post-dose FEV1 measurements collected on that day, which included pre-dose (Day 1: 30 minutes \[min\] and 5 min prior to dosing; other serial visits: 23 and 24 hours after the previous morning dose) and post-dose at 15 min, 30 min, 1 hour, 3 hours, and 6 hours. Change from Baseline at a particular visit was calculated as the WM at that visit minus Baseline. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the two assessments made 30 min and 5 min pre-dose on Day 1), smoking status, center group, day, and day by Baseline and day by treatment interactions. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24 | Baseline and Week 24 | The newly developed SOBDA questionnaire assesses dyspnea or shortness of breath (SOB) with daily activities. The SOBDA questionnaire is made up of 13 items completed by the participant (par.) each evening prior to bedtime, when the par. is instructed to reflect on the current day's activities. The daily score is computed as the mean of the scores on the 13 items (\>=7 items must have non-missing responses for this to be calculated). The par. is assigned a weekly mean SOBDA score ranging from 1 to 4 (greater scores indicate more severe breathlessness with daily activities) based on the mean of 7 days of data (\>=4 of 7 days must be completed for a weekly mean to be calculated). Change from BL is the mean weekly SOBDA score minus BL. Analysis was performed using MMRM with covariates of treatment, BL (mean score in the week prior to treatment), smoking status, center group, week, week by BL and week by treatment interactions. This MMRM analysis only included Weeks 4, 8, 12, and 24. |
Countries
Belgium, Denmark, Estonia, France, Germany, Hungary, Japan, Netherlands, Norway, Philippines, Slovakia, Sweden, Ukraine, United States
Participant flow
Pre-assignment details
Participants (par.) who met eligibility criteria at Screening (Visit 1) completed a 7- to14-day run-in period and were then randomized to a 24-week treatment (trt.) period. A total of 2114 participants were screened; 1493 participants were randomized, and 1489 participants took at least one dose of randomized medication.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received matching placebo once daily (QD) via a dry powder inhaler (DPI) in the morning for 24 weeks. | 275 |
| UMEC 125 µg Participants received UMEC 125 µg QD via a DPI in the morning for 24 weeks. | 407 |
| VI 25 µg Participants received VI 25 µg QD via a DPI for 24 weeks. | 404 |
| UMEC/VI 125/25 µg Participants received UMEC/VI 125/25 µg QD via a DPI in the morning for 24 weeks. | 403 |
| Total | 1,489 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 17 | 24 | 25 | 18 |
| Overall Study | Lack of Efficacy | 44 | 38 | 37 | 24 |
| Overall Study | Lost to Follow-up | 0 | 2 | 1 | 3 |
| Overall Study | Met Protocol- Defined Stopping Criteria | 16 | 15 | 14 | 13 |
| Overall Study | Protocol Violation | 4 | 3 | 11 | 5 |
| Overall Study | Withdrawal by Subject | 11 | 13 | 18 | 15 |
Baseline characteristics
| Characteristic | Placebo | UMEC 125 µg | VI 25 µg | UMEC/VI 125/25 µg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.2 Years STANDARD_DEVIATION 8.53 | 63.1 Years STANDARD_DEVIATION 8.48 | 62.8 Years STANDARD_DEVIATION 8.8 | 63.4 Years STANDARD_DEVIATION 8.08 | 62.9 Years STANDARD_DEVIATION 8.47 |
| Race/Ethnicity, Customized African American/African Heritage | 9 Participants | 4 Participants | 7 Participants | 4 Participants | 24 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 13 Participants | 21 Participants | 21 Participants | 19 Participants | 74 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 14 Participants | 19 Participants | 20 Participants | 20 Participants | 73 Participants |
| Race/Ethnicity, Customized Mixed Race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 237 Participants | 361 Participants | 353 Participants | 359 Participants | 1310 Participants |
| Sex: Female, Male Female | 100 Participants | 137 Participants | 139 Participants | 139 Participants | 515 Participants |
| Sex: Female, Male Male | 175 Participants | 270 Participants | 265 Participants | 264 Participants | 974 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 63 / 275 | 97 / 407 | 113 / 404 | 102 / 403 |
| serious Total, serious adverse events | 17 / 275 | 22 / 407 | 20 / 404 | 23 / 403 |
Outcome results
Primary
Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24)
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 measurements were taken electronically by spirometry on Days 2, 28, 56, 84, 112, 168, and 169. Baseline is defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Trough FEV1 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous morning's dosing (ie., trough FEV1 on Day 169 is the mean of the FEV1 values obtained 23 and 24 hours after the morning dosing on Day 168). Change from Baseline at a particular visit was calculated as the trough FEV1 at that visit minus Baseline. Analysis was performed using a repeated measures model with covariates of treatment, Baseline , smoking status, center group, day, and day by Baseline and day by treatment interactions. ITT=Intent-to-Treat; par.=participants.
Time frame: Baseline and Day 169
Population: Intent-to-Treat (ITT) Population: all par. randomized to trt. who received at least one dose of randomized study drug. Par. represents those with data available at the time point being presented; however, all par. in the ITT population without missing covariate information and with at least one post BL measurement are included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24) | -0.031 Liters | Standard Error 0.0153 |
| UMEC 125 µg | Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24) | 0.129 Liters | Standard Error 0.0119 |
| VI 25 µg | Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24) | 0.093 Liters | Standard Error 0.0121 |
| UMEC/VI 125/25 µg | Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24) | 0.207 Liters | Standard Error 0.0119 |
p-value: <0.00195% CI: [0.122, 0.198]Mixed Models Analysis
p-value: <0.00195% CI: [0.086, 0.162]Mixed Models Analysis
p-value: <0.00195% CI: [0.2, 0.276]Mixed Models Analysis
p-value: <0.00195% CI: [0.046, 0.112]Mixed Models Analysis
p-value: <0.00195% CI: [0.081, 0.148]Mixed Models Analysis
Secondary
Change From Baseline in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168
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 WM 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 WM was calculated at Days 1, 28, 84, and 168 using the 0-6-hour post-dose FEV1 measurements collected on that day, which included pre-dose (Day 1: 30 minutes \[min\] and 5 min prior to dosing; other serial visits: 23 and 24 hours after the previous morning dose) and post-dose at 15 min, 30 min, 1 hour, 3 hours, and 6 hours. Change from Baseline at a particular visit was calculated as the WM at that visit minus Baseline. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the two assessments made 30 min and 5 min pre-dose on Day 1), smoking status, center group, day, and day by Baseline and day by treatment interactions.
Time frame: Baseline and Day 168
Population: Intent-to-Treat (ITT) Population: all par. randomized to trt. who received at least one dose of randomized study drug. Par. represents those with data available at the time point being presented; however, all par. in the ITT population without missing covariate information and with at least one post BL measurement are included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168 | -0.018 Liters | Standard Error 0.015 |
| UMEC 125 µg | Change From Baseline in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168 | 0.160 Liters | Standard Error 0.0118 |
| VI 25 µg | Change From Baseline in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168 | 0.127 Liters | Standard Error 0.0119 |
| UMEC/VI 125/25 µg | Change From Baseline in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168 | 0.269 Liters | Standard Error 0.0118 |
Secondary
Mean Transition Dyspnea Index (TDI) Focal Score at Day 168 (Week 24)
Considered an 'other' endpoint by the FDA. The TDI is an interviewer-administered instrument which measures the changes in the participant's dyspnea from Baseline. This questionnaire was collected on Days 28, 84 and 168. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9. Analysis was performed using a repeated measures model with covariates of treatment, Baseline dyspnea index (BDI) focal score,smoking status, center group, day, day by BDI focal score and day by treatment interactions.
Time frame: Day 168 (Week 24)
Population: Intent-to-Treat (ITT) Population: all par. randomized to trt. who received at least one dose of randomized study drug. Par. represents those with data available at the time point being presented; however, all par. in the ITT population without missing covariate information and with at least one post BL measurement are included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Transition Dyspnea Index (TDI) Focal Score at Day 168 (Week 24) | 0.8 Scores on a scale | Standard Error 0.2 |
| UMEC 125 µg | Mean Transition Dyspnea Index (TDI) Focal Score at Day 168 (Week 24) | 1.2 Scores on a scale | Standard Error 0.16 |
| VI 25 µg | Mean Transition Dyspnea Index (TDI) Focal Score at Day 168 (Week 24) | 1.3 Scores on a scale | Standard Error 0.16 |
| UMEC/VI 125/25 µg | Mean Transition Dyspnea Index (TDI) Focal Score at Day 168 (Week 24) | 1.8 Scores on a scale | Standard Error 0.15 |
Other Pre-specified
Change From Baseline in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24
The newly developed SOBDA questionnaire assesses dyspnea or shortness of breath (SOB) with daily activities. The SOBDA questionnaire is made up of 13 items completed by the participant (par.) each evening prior to bedtime, when the par. is instructed to reflect on the current day's activities. The daily score is computed as the mean of the scores on the 13 items (\>=7 items must have non-missing responses for this to be calculated). The par. is assigned a weekly mean SOBDA score ranging from 1 to 4 (greater scores indicate more severe breathlessness with daily activities) based on the mean of 7 days of data (\>=4 of 7 days must be completed for a weekly mean to be calculated). Change from BL is the mean weekly SOBDA score minus BL. Analysis was performed using MMRM with covariates of treatment, BL (mean score in the week prior to treatment), smoking status, center group, week, week by BL and week by treatment interactions. This MMRM analysis only included Weeks 4, 8, 12, and 24.
Time frame: Baseline and Week 24
Population: Intent-to-Treat (ITT) Population: all par. randomized to trt. who received at least one dose of randomized study drug. Par. represents those with data available at the time point being presented; however, all par. in the ITT population without missing covariate information and with at least one post BL measurement are included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24 | -0.07 Scores on a scale | Standard Error 0.038 |
| UMEC 125 µg | Change From Baseline in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24 | -0.15 Scores on a scale | Standard Error 0.029 |
| VI 25 µg | Change From Baseline in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24 | -0.10 Scores on a scale | Standard Error 0.029 |
| UMEC/VI 125/25 µg | Change From Baseline in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24 | -0.22 Scores on a scale | Standard Error 0.029 |