Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
long-acting muscarinic antagonist, tiotropium, COPD, long-acting beta agonist
Brief summary
This is a Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of two doses of GSK573719/GW642444 Inhalation Powder and GW642444 Inhalation Powder via a Novel Dry Powder Inhaler and tiotropium via HandiHaler when administered once-daily over a 24-week treatment period in subjects with chronic obstructive pulmonary disease (COPD). Subjects who meet eligibility criteria at Screening (Visit 1) will complete a 7 to10 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 26 weeks. The primary measure of efficacy is clinic visit trough (pre-bronchodilator and pre-dose) forced expiratory volume in one second (FEV1) on Treatment Day 169. Safety will be assessed by adverse events, 12-lead ECGs, vital signs, and clinical laboratory tests.
Detailed description
This is a 24-week, Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study. Eligible subjects will be randomized to GSK573719/GW642444 125/25mcg, GSK573719/GW642444 62.5/25mcg, GW642444 25mcg, or tiotropium treatment groups in a 1:1:1:1 ratio. Treatments will be administered once-daily in the morning by inhalation using a Novel Dry Powder Inhaler (Novel DPI) and HandiHaler. 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 10 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 26 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/forced vital capacity (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, 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 morning and the evening throughout the run-in and treatment periods. Subjects will use the eDiary to record peak expiratory flow (PEF) each morning, 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. General health status will be evaluated using the subject-completed EQ-5D questionnaire at Visits 2, 4, 6, and 8. Disease specific health status will be evaluated using the subject-completed St. George's Respiratory Questionnaire (SGRQ) at Visits 2, 4, 6, and 8, and the subject-completed COPD Assessment Test (CAT) at Visits 2, 6, and 8. 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.
Interventions
125/25 mcg once-daily
62.5/26 mcg once-daily
DRUGGW642444
25 mcg once-daily
DRUGtiotropium bromide
18 mcg once-daily
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
* outpatient * signed and dated written informed consent * 40 years of age or older * male and female subjects * COPD diagnosis * at least 10 pack-year smoking history * post-albuterol/salbutamol FEV1/FVC ratio of \<0.70 and post-albuterol/salbutamol FEV1 of less than or equal to 70% predicted normal values * score of greater than or equal to 2 on the Modified Medical Resarch Council Dyspnea Scale (mMRC)
Exclusion criteria
* women who are pregnant or lactating or are planning on becoming pregnant during the study * current diagnosis of asthma * other respiratory disorders other than COPD * other diseases/abnormalities that are uncontrolled including cancer not in remission for at least 5 years * chest x-ray or CT scan with clinically significant abnormalities not believed to be due to COPD * hypersensitivity to anticholinergics, beta-agonists, lactose/milk protein or magnesium stearate or medical conditions associated with inhaled anticholinergics * hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1 * lung volume reduction surgery within 12 months prior to Visit 1 * abnormal and clinically significant ECG at Visit 1 * significantly abnormal finding from laboratory tests at Visit 1 * unable to withhold albuterol/salbutamol at least 4 hours prior to spirometry at each visit * use of depot corticosteroids within 12 weeks of Visit 1 * use of oral or parenteral corticosteroids, antibiotics for lower respiratory tract infection, or cytochrome P450 3A4 inhibitors, within 6 weeks of Visit 1 * use of long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) product if LABA/ICS therapy is discontinued withing 30 days of Visit 1 * use of ICS at a dose of \>1000mcg/day of fluticasone propionate or equivalent within 30 days of Visit 1 * initiation or discontinuation of ICS within 30 days of Visit 1 * use of tiotropium or roflumilast within 14 days of Visit 1 * use of theophyllines, oral leukotriene inhibitors, long-acting oral beta-agonists, or inhaled long-acting beta-agonists within 48 hours of Visit 1 * short-acting oral beta-agonists within 12 hours of Visit 1 * use of LABA/ICS combination products only if discontinuing LABA therapy and switching to ICS monotherapy within 48 hours of Visit 1 for the LABA component * use of sodium cromoglycate or nedocromil sodium within 24 hours of Visit 1 * use of inhaled short-acting beta-agonists, inhaled short-acting anticholinergics, or inhaled short-acting anticholinergic/short-acting beta-agonist combination products within 4 hours of Visit 1 * use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer) * long-term oxygen therapy prescribed for \>12 hours per day * regular use of nebulized short-acting bronchodilators * participation in acute phase of pulmonary rehabilitation program * known or suspected history of alcohol or drug abse within 2 years prior to Visit 1 * anyone affiliated with the investigator site (e.g., investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member) * previous exposure to GSK573719, GSK573719/GW642444 combination, GW642444 (vilanterol), or fluticasone furoate/GW642444 combination
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 |
|---|---|---|
| Change From Baseline (BL) 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, 84, and Day 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 minutes, 30 minutes, 1 hour, 3 hours, and 6 hours. Change from BL at a particular visit was calculated as WM at that visit minus BL. Analysis was performed using a repeated measures model with covariates of treatment, BL (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, center group, day, and day by BL and day by treatment interactions. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (BL) 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
France, Germany, Italy, Mexico, Peru, Poland, Romania, Russia, Ukraine, United States
Participant flow
Pre-assignment details
Participants (par.) who met eligibility criteria at Screening (Visit 1) completed a 7- to10-day run-in period and were then randomized to a 24-week treatment period. A total of 1141 par. were screened; 846 par. were randomized (3 par. were randomized \[2 in error\] and received no study drug) and 843 par. received at least one dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| VI 25 µg Participants received vilanterol (VI) 25 micrograms (µg) once daily (QD) via a dry powder inhaler (DPI). All participants also received placebo QD via a HandiHaler. | 209 |
| UMEC/VI 62.5/25 µg Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler. | 212 |
| UMEC/VI 125/25 µg Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler. | 214 |
| Tiotropium 18 µg Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI. | 208 |
| Total | 843 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 10 | 15 | 9 |
| Overall Study | Lack of Efficacy | 17 | 9 | 5 | 7 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 | 1 |
| Overall Study | Protocol-defined Stopping Criteria | 2 | 3 | 10 | 5 |
| Overall Study | Protocol Violation | 7 | 1 | 4 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 8 | 6 | 9 |
Baseline characteristics
| Characteristic | VI 25 µg | Total | Tiotropium 18 µg | UMEC/VI 125/25 µg | UMEC/VI 62.5/25 µg |
|---|---|---|---|---|---|
| Age, Continuous | 63.2 Years STANDARD_DEVIATION 9.1 | 62.9 Years STANDARD_DEVIATION 9 | 62.6 Years STANDARD_DEVIATION 9.39 | 62.9 Years STANDARD_DEVIATION 8.87 | 63.0 Years STANDARD_DEVIATION 8.67 |
| Race/Ethnicity, Customized African American/African Heritage | 3 participants | 25 participants | 6 participants | 9 participants | 7 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 19 participants | 76 participants | 20 participants | 21 participants | 16 participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 0 participants | 5 participants | 2 participants | 0 participants | 3 participants |
| Race/Ethnicity, Customized Mixed Race | 3 participants | 13 participants | 3 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 184 participants | 723 participants | 177 participants | 180 participants | 182 participants |
| Sex: Female, Male Female | 66 Participants | 261 Participants | 68 Participants | 63 Participants | 64 Participants |
| Sex: Female, Male Male | 143 Participants | 582 Participants | 140 Participants | 151 Participants | 148 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 | 44 / 209 | 54 / 212 | 40 / 214 | 37 / 208 |
| serious Total, serious adverse events | 15 / 209 | 7 / 212 | 5 / 214 | 13 / 208 |
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: ITT Population excluding par. from Investigator 040688: all randomized par. who received \>=1 dose of study drug, except for those from Investigator 040688. Par. analyzed are those with data available at the presented time point; but, all par. without missing covariate information and with \>=1 post-BL measurement were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VI 25 µg | Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24) | 0.121 Liters | Standard Error 0.0189 |
| UMEC/VI 62.5/25 µg | Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24) | 0.211 Liters | Standard Error 0.0183 |
| UMEC/VI 125/25 µg | Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24) | 0.209 Liters | Standard Error 0.0187 |
| TIO 18 µg | Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24) | 0.121 Liters | Standard Error 0.0186 |
p-value: <0.00195% CI: [0.039, 0.142]Mixed Models Analysis
p-value: <0.00195% CI: [0.039, 0.141]Mixed Models Analysis
p-value: <0.00195% CI: [0.036, 0.14]Mixed Models Analysis
p-value: <0.00195% CI: [0.036, 0.14]Mixed Models Analysis
Secondary
Change From Baseline (BL) 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, 84, and Day 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 minutes, 30 minutes, 1 hour, 3 hours, and 6 hours. Change from BL at a particular visit was calculated as WM at that visit minus BL. Analysis was performed using a repeated measures model with covariates of treatment, BL (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, center group, day, and day by BL and day by treatment interactions.
Time frame: Baseline and Day 168
Population: ITT Population excluding participants from Investigator 040688. Par. analyzed are those with data available at the presented time point; but, all par. without missing covariate information and with \>=1 post-Baseline measurement were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VI 25 µg | Change From Baseline (BL) in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168 | 0.178 Liters | Standard Error 0.0189 |
| UMEC/VI 62.5/25 µg | Change From Baseline (BL) in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168 | 0.254 Liters | Standard Error 0.0183 |
| UMEC/VI 125/25 µg | Change From Baseline (BL) in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168 | 0.263 Liters | Standard Error 0.0187 |
| TIO 18 µg | Change From Baseline (BL) in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168 | 0.181 Liters | Standard Error 0.0187 |
Other Pre-specified
Change From Baseline (BL) 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: ITT Population excluding participants from Investigator 040688. Participants analyzed are those with data available at the presented time point; but, all participants without missing covariate information and with \>=1 post-Baseline measurement were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VI 25 µg | Change From Baseline (BL) in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24 | -0.16 Scores on a scale | Standard Error 0.043 |
| UMEC/VI 62.5/25 µg | Change From Baseline (BL) in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24 | -0.18 Scores on a scale | Standard Error 0.042 |
| UMEC/VI 125/25 µg | Change From Baseline (BL) in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24 | -0.18 Scores on a scale | Standard Error 0.044 |
| TIO 18 µg | Change From Baseline (BL) in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24 | -0.18 Scores on a scale | Standard Error 0.044 |