Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
This is a phase III multicenter, randomized, double-blind, placebo-controlled, combination and component, two-period, incomplete block design cross-over study using GSK573719/GW642444. The primary objective is to evaluate lung function and exercise endurance time after 12 weeks of once-daily administration of GSK573719/GW642444 Inhalation Powder (125/25mcg and 62.5/25mcg), GSK573719 Inhalation Powder (125mcg and 62.5mcg), GW642444 Inhalation Powder 25 mcg and placebo delivered by a Novel dry powder inhaler (Novel DPI)
Detailed description
Expiratory airflow limitation is the most obvious physiological change associated with chronic obstructive pulmonary disease (COPD). A consequence of airflow limitation is gas trapping as expiration becomes flow limited. This may occur at rest with more severe airway obstruction and is most evident during exercise as lung emptying is reduced and increased ventilation does not allow full expiration. This increased gas trapping or hyperinflation is the cause of much of the increased work of breathing, dyspnea, and exercise intolerance in subjects with COPD (O'Donnell 1997; O'Donnell, 1993). Spirometric measurement of airflow limitation, particularly as assessed by forced expiratory volume in one second (FEV1), is commonly used for the diagnosis of and assessment of response to pharmacotherapeutic intervention in COPD. However, changes in FEV1 may not fully predict symptomatic responses and alternative measures of lung hyperinflation such as exercise tolerance and exertional dyspnea may be more sensitive to therapeutic intervention and/or more clinically relevant than FEV1 \[O'Donnell1999; Bauerle, 1998; O'Donnell, 1998; Officer, 1998\]. GSK573719/GW642444 Inhalation Powder, a combination of the long-acting muscarinic antagonist (LAMA) bronchodilator GSK573719 and the long-acting beta2-agonist (LABA) bronchodilator GW642444, is in development for the maintenance treatment of airflow obstruction associated with COPD. Development of this product is supported by studies showing improvement in lung function with similar safety when use of combinations of long-acting bronchodilators with different mechanisms of action are compared with single bronchodilator therapy \[van Noord 2005; van Noord van Noord 2006; Tashkin 2008\]. Previous studies have demonstrated that treatment with short- and long-acting bronchodilators including ipratropium, tiotropium, and salmeterol reduces resting lung hyperinflation as measured by functional residual capacity (FRC), residual volume (RV), and inspiratory capacity (IC), with associated improvements in exercise endurance time and exertional dyspnoea in subjects with COPD \[Ayers, 2001; O'Donnell 1998; O'Donnell 2004; Pepin 2005; Pepin 2007; Ramirez-Venegas 1997\]. However, the effect of combined LAMA/LABA therapy on these measures is not well characterized. This is a phase III multicenter, randomized, double-blind, placebo-controlled, combination and component, two-period, incomplete block design cross-over study using GSK573719/GW642444. The primary objective is to evaluate lung function and exercise endurance time after 12 weeks of once-daily administration of GSK573719/GW642444 Inhalation Powder (125/25mcg and 62.5/25mcg), GSK573719 Inhalation Powder (125mcg and 62.5mcg), GW642444 Inhalation Powder 25 mcg and placebo delivered by a Novel dry powder inhaler (Novel DPI) Approximately 312 subjects with moderate/severe chronic obstructive pulmonary disease (COPD) will be randomised in order to achieve 208 subjects completing both treatment periods of 3 months.. There will be a total of 12 study clinic visits conducted on an outpatient basis. Subjects who meet the eligibility criteria at Screening (Visit 1) will complete a 12 to 21 day run-in period followed by two 12-week treatment periods that are separated by a 14 day wash-out. Clinic visits will be conducted at Screening (Visit 1), twice during the run-in period (Visits 2 and 3), at randomization (Visit 4) and three times during the first treatment period, on Treatment Day 2 (Visit 5) and at 6 and 12 weeks (Visits 6 and 7 respectively). During the washout period of 14 days there will be 2 clinic visits (Visits 8 and 9). During the second treatment period there will be 3 clinic visits, on Treatment Day 2 (Visit 10) and at 6 and 12 weeks (Visits 11 and 12 respectively). A Safety Follow-Up assessment (Visit 13) to record adverse events will be conducted by telephone 7 days after the end of the second treatment period or early withdrawal. Efficacy measurements will include pre and post dose FEV1, lung volume measurements and exercise endurance time measured using the endurance shuttle walking test (ESWT). Oxycon mobile measurements will be conducted in a subgroup of approximately 104 patients to investigate cardio respiratory measures during exercise. Safety and tolerability will be assessed by collection of adverse events (AEs), vital signs, 12-lead electrocardiograms (ECGs), clinical laboratory tests and incidence of COPD exacerbations. Dyspnea will be assessed using the Exercise Dyspnea Scale (EDS), a patient-reported outcome. Blood samples will also be collected for potential pharmacogenetics analysis
Interventions
DRUGGSK 573719 +GW642444 125/25
125mcg/ 25mcg
DRUGGSK573719 + GW642444 62.5/25
62.5mcg/25mcg
DRUGGSK 573719 125
125mcg
DRUGGSK 573719 62.5
62.5mcg
DRUGGW642444 25
25mcg
DRUGPlb
Comparator
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type of subject: Outpatient. * Informed Consent: A signed and dated written informed consent prior to study participation. * Age: 40 years of age or older at Visit 1. * Gender: Male or female subjects. * Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society \[Celli, 2004\] * Smoking History: Current or former cigarette smokers with a history of cigarette smoking of ≥ 10 pack-years * Severity of Disease: A post-albuterol/salbutamol FEV1/FVC ratio of \<0.70 and a post-albuterol/salbutamol FEV1 of \>35% and \<70% of predicted normal * Dyspnea: A score of ≥2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1 * Resting Lung Volumes: A resting FRC of ≥120% of predicted normal FRC at Visit 1.
Exclusion criteria
* Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study. * Asthma: A current diagnosis of asthma. * Other Respiratory Disorders: Known respiratory disorders other than COPD including but not limited to alpha-1 antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, and interstitial lung disease. Allergic rhinitis is not exclusionary. * Other Diseases/Abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for \< 5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. Any physical or mental abnormality which would affect the patient carrying out exercise tests including peripheral vascular disease should be excluded at the investigators discretion. * Chest X-Ray: A chest X-ray or computed tomography (CT) scan that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken at Visit 1 if a chest X-ray or CT scan is not available within 6 months prior to Visit 1. For subjects in Germany, if a chest X-ray (or CT scan) is not available in the 6 months prior to Visit 1 the subject will not be eligible for the study. * Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the study physician contraindicates study participation or use of an inhaled anticholinergic. * Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1. * Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1). * 12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1, including the presence of a paced rhythm on a 12-lead electrocardiogram (ECG) which causes the underlying rhythm and ECG to be obscured. Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. * Screening Labs: Significantly abnormal finding from clinical chemistry and hematology tests at Visit 1. * Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit. * Medications prior to Screening, including depot,oral corticosteroids, combinations of LABA/ICS, LABA, PDE4 inhibitors. * Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., \<12 hours per day) is not exclusionary. * Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy * Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded. * Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1. * Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Exercise Endurance Time Post-dose at Week 12 of Each Treatment Period | Week 12 of each treatment period (up to Study Week 29) | Exercise endurance time (EET) post-dose at Week 12 is defined as the EET obtained 3 hours after dosing at Week 12. EET was measured using the externally paced field walking test called the endurance shuttle walk test (ESWT). Analysis performed using a repeated measures model with covariates of period walking speed, mean walking speed, period, treatment, visit, smoking status, center group, visit by period walking speed, visit by mean walking speed and visit by treatment interactions. The model used all available 3-hour post-dose change from baseline EET values recorded on Day 2, Week 6 and Week 12. Baseline was the EET assessment obtained prior to dosing on Day 1 of each period. The mean walking speed for each participant is the mean of the levels used for the ESWT in each of the two treatment periods. The period walking speed for each participant and treatment period is the difference between the level for that participant and period and the mean walking speed for that participant. |
| Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 12 of Each Treatment Period | Week 12 of each treatment period (up to Study Week 29) | 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 Day 2, Week 6 and Week 12. Baseline is the FEV1 value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at Week 12 (Treatment Day 85) is defined as the FEV1 value obtained 24 hours after dosing on Treatment Day 84. Analysis performed using a repeated measures model with covariates of period Baseline, mean Baseline, period, treatment, visit, smoking status, center group, visit by period Baseline, visit by mean Baseline and visit by treatment interactions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Week 12 of each treatment period (up to Study Week 29) | Inspiratory capacity (IC) is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Baseline is the IC value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Trough IC is measured pre-dose on Treatment Week 12 of each treatment period. IC 3-hours post-dose is measured from the value obtained 3 hours after dosing on Treatment Week 12 of each treatment period. Analysis performed using a repeated measures model with covariates of period Baseline, mean Baseline, period, treatment, visit, smoking status, center group, visit by period Baseline, visit by mean Baseline and visit by treatment interactions. IC measurements were taken electronically by plethysmography on Day 2, Week 6 and Week 12. |
| Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Week 12 of each treatment period (up to Study Week 29) | Functional Residual Capacity (FRC) is defined as the amount of air still left in the lungs after breathing out normally. Baseline is the FRC value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Trough FRC is measured pre-dose on Treatment Week 12. FRC 3-hours post-dose is measured from the value obtained 3 hours after dosing on Treatment Week 12. Analysis performed using a repeated measures model with covariates of period Baseline, mean Baseline, period, treatment, visit, smoking status, center group, visit by period Baseline, visit by mean Baseline and visit by treatment interactions. FRC measurements were taken electronically by plethysmography on Day 2, Week 6 and Week 12. |
| Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Week 12 of each treatment period (up to Study Week 29) | Residual Volume (RV) is defined as the air that remains in the lungs after breathing out as fully as possible. Baseline is the RV value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Trough RV is measured pre-dose on Treatment Week 12. RV 3-hours post-dose is measured from the value obtained 3 hours after dosing on Treatment Week 12. Analysis performed using a repeated measures model with covariates of period Baseline, mean Baseline, period, treatment, visit, smoking status, center group, visit by period Baseline, visit by mean Baseline and visit by treatment interactions. RV measurements were taken electronically by plethysmography on Day 2, Week 6 and Week 12. |
| Change From Baseline in 3-hours Post-dose FEV1 at Week 12 of Each Treatment Period | Week 12 of each treatment period (up to Study Week 29) | FEVI is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Baseline is the FEV1 value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Clinic visit post-dose FEV1 at Week 12 (Treatment Day 85) is defined as the FEV1 value obtained 3 hours after dosing on Treatment Day 85. Analysis performed using a repeated measures model with covariates of period Baseline, mean Baseline, period, treatment, visit, smoking status, center group, visit by period Baseline, visit by mean Baseline and visit by treatment interactions 3 hour post-dose FEV1 measurements were taken electronically by spirometry on Day 2, Week 6 and Week 12. |
Countries
Bulgaria, Estonia, Germany, Russia, United Kingdom, United States
Participant flow
Recruitment details
Participants (par.) who were eligible completed a 12- to 21-day Run-in Period followed by two 12-week treatment periods.
Pre-assignment details
A total of 596 par. were enrolled and screened, 409 par. entered the Run-in Period, 349 par. were randomized and 348 par. received study treatment. Participant Flow data are presented by treatment rather than sequence. Par. received 2 out of the 6 interventions.
Participants by arm
| Arm | Count |
|---|---|
| All Study Treatments Participants were randomized to receive a sequence consisting of 2 of the following treatments: UMEC/VI 125/25 µg , UMEC/VI 62.5/25 µg , UMEC 125 µg , UMEC 62.5 µg , VI 25 µg , or placebo QD via a DPI. Each treatment was administered in the morning for 12 weeks. The treatment periods were seperated by 14-day washout period. | 348 |
| Total | 348 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 (12 Weeks) | Adverse Event | 3 | 1 | 1 | 3 | 5 | 2 |
| Treatment Period 1 (12 Weeks) | Lack of Efficacy | 6 | 1 | 1 | 1 | 6 | 2 |
| Treatment Period 1 (12 Weeks) | Lost to Follow-up | 2 | 0 | 0 | 1 | 0 | 1 |
| Treatment Period 1 (12 Weeks) | Met Protocol- Defined Stopping Criteria | 0 | 1 | 0 | 0 | 2 | 0 |
| Treatment Period 1 (12 Weeks) | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 1 |
| Treatment Period 1 (12 Weeks) | Withdrawal by Subject | 0 | 2 | 1 | 2 | 1 | 0 |
| Treatment Period 2 (12 Weeks) | Adverse Event | 5 | 0 | 1 | 1 | 1 | 0 |
| Treatment Period 2 (12 Weeks) | Lack of Efficacy | 5 | 1 | 1 | 2 | 3 | 4 |
| Treatment Period 2 (12 Weeks) | Lost to Follow-up | 0 | 0 | 1 | 1 | 1 | 2 |
| Treatment Period 2 (12 Weeks) | Met Protocol Defined Stopping Criteria | 0 | 0 | 0 | 1 | 1 | 0 |
| Treatment Period 2 (12 Weeks) | Protocol Violation | 1 | 0 | 0 | 0 | 1 | 0 |
| Treatment Period 2 (12 Weeks) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 1 |
| Washout Period (14 Days) | Adverse Event | 1 | 1 | 0 | 1 | 1 | 2 |
| Washout Period (14 Days) | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 1 |
| Washout Period (14 Days) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | All Study Treatments |
|---|---|
| Age, Continuous | 61.6 Years STANDARD_DEVIATION 8.25 |
| Race/Ethnicity, Customized African American/African Heritage | 11 Participants |
| Race/Ethnicity, Customized Mixed Race | 1 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 336 Participants |
| Sex: Female, Male Female | 153 Participants |
| Sex: Female, Male Male | 195 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 170 | 1 / 49 | 5 / 50 | 7 / 76 | 8 / 152 | 8 / 144 |
| serious Total, serious adverse events | 6 / 170 | 0 / 49 | 3 / 50 | 7 / 76 | 4 / 152 | 4 / 144 |
Outcome results
Primary
Change From Baseline in Exercise Endurance Time Post-dose at Week 12 of Each Treatment Period
Exercise endurance time (EET) post-dose at Week 12 is defined as the EET obtained 3 hours after dosing at Week 12. EET was measured using the externally paced field walking test called the endurance shuttle walk test (ESWT). Analysis performed using a repeated measures model with covariates of period walking speed, mean walking speed, period, treatment, visit, smoking status, center group, visit by period walking speed, visit by mean walking speed and visit by treatment interactions. The model used all available 3-hour post-dose change from baseline EET values recorded on Day 2, Week 6 and Week 12. Baseline was the EET assessment obtained prior to dosing on Day 1 of each period. The mean walking speed for each participant is the mean of the levels used for the ESWT in each of the two treatment periods. The period walking speed for each participant and treatment period is the difference between the level for that participant and period and the mean walking speed for that participant.
Time frame: Week 12 of each treatment period (up to Study Week 29)
Population: Intent-to-Treat (ITT) Population: all par. randomized to treatment who received at least one dose of study drug in either treatment period. Number of par. represent those with data available at the time point; however, all par. in the ITT population without missing covariate information and with at least one post Baseline measurement are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Exercise Endurance Time Post-dose at Week 12 of Each Treatment Period | 36.7 Seconds | Standard Error 13.17 |
| UMEC 62.5 µg QD | Change From Baseline in Exercise Endurance Time Post-dose at Week 12 of Each Treatment Period | 63.2 Seconds | Standard Error 23.93 |
| UMEC 125 µg QD | Change From Baseline in Exercise Endurance Time Post-dose at Week 12 of Each Treatment Period | 49.8 Seconds | Standard Error 23.77 |
| VI 25 µg QD | Change From Baseline in Exercise Endurance Time Post-dose at Week 12 of Each Treatment Period | 26.7 Seconds | Standard Error 19.72 |
| UMEC/VI 62.5/25 µg QD | Change From Baseline in Exercise Endurance Time Post-dose at Week 12 of Each Treatment Period | 58.6 Seconds | Standard Error 13.82 |
| UMEC/VI 125/25 µg QD | Change From Baseline in Exercise Endurance Time Post-dose at Week 12 of Each Treatment Period | 69.1 Seconds | Standard Error 13.99 |
p-value: 0.32195% CI: [-25.9, 78.9]Mixed Models Analysis
p-value: 0.6295% CI: [-38.9, 65.1]Mixed Models Analysis
p-value: 0.66595% CI: [-55.5, 35.4]Mixed Models Analysis
p-value: 0.86595% CI: [-57.6, 48.4]Mixed Models Analysis
p-value: 0.17495% CI: [-14.1, 77.9]Mixed Models Analysis
p-value: 0.47295% CI: [-33.4, 71.9]Mixed Models Analysis
p-value: 0.07295% CI: [-3.8, 88.7]Mixed Models Analysis
p-value: 0.23495% CI: [-14.2, 58]Mixed Models Analysis
p-value: 0.0895% CI: [-3.9, 68.8]Mixed Models Analysis
Primary
Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 12 of Each Treatment Period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 measurements were taken electronically by spirometry on Day 2, Week 6 and Week 12. Baseline is the FEV1 value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at Week 12 (Treatment Day 85) is defined as the FEV1 value obtained 24 hours after dosing on Treatment Day 84. Analysis performed using a repeated measures model with covariates of period Baseline, mean Baseline, period, treatment, visit, smoking status, center group, visit by period Baseline, visit by mean Baseline and visit by treatment interactions.
Time frame: Week 12 of each treatment period (up to Study Week 29)
Population: Intent-to-Treat (ITT) Population: all par. randomized to treatment who received at least one dose of study drug in either treatment period. Number of par. represent those with data available at the time point; however, all par. in the ITT population without missing covariate information and with at least one post Baseline measurement are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 12 of Each Treatment Period | -0.032 Liters | Standard Error 0.0149 |
| UMEC 62.5 µg QD | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 12 of Each Treatment Period | 0.054 Liters | Standard Error 0.0264 |
| UMEC 125 µg QD | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 12 of Each Treatment Period | 0.108 Liters | Standard Error 0.0263 |
| VI 25 µg QD | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 12 of Each Treatment Period | 0.067 Liters | Standard Error 0.0218 |
| UMEC/VI 62.5/25 µg QD | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 12 of Each Treatment Period | 0.178 Liters | Standard Error 0.0156 |
| UMEC/VI 125/25 µg QD | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 12 of Each Treatment Period | 0.136 Liters | Standard Error 0.0158 |
p-value: 0.00395% CI: [0.03, 0.143]Mixed Models Analysis
p-value: <0.00195% CI: [0.084, 0.196]Mixed Models Analysis
p-value: <0.00195% CI: [0.05, 0.148]Mixed Models Analysis
p-value: <0.00195% CI: [0.067, 0.181]Mixed Models Analysis
p-value: <0.00195% CI: [0.062, 0.161]Mixed Models Analysis
p-value: 0.3295% CI: [-0.028, 0.086]Mixed Models Analysis
p-value: 0.00795% CI: [0.019, 0.12]Mixed Models Analysis
p-value: <0.00195% CI: [0.172, 0.249]Mixed Models Analysis
p-value: <0.00195% CI: [0.129, 0.209]Mixed Models Analysis
Secondary
Change From Baseline in 3-hours Post-dose FEV1 at Week 12 of Each Treatment Period
FEVI is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Baseline is the FEV1 value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Clinic visit post-dose FEV1 at Week 12 (Treatment Day 85) is defined as the FEV1 value obtained 3 hours after dosing on Treatment Day 85. Analysis performed using a repeated measures model with covariates of period Baseline, mean Baseline, period, treatment, visit, smoking status, center group, visit by period Baseline, visit by mean Baseline and visit by treatment interactions 3 hour post-dose FEV1 measurements were taken electronically by spirometry on Day 2, Week 6 and Week 12.
Time frame: Week 12 of each treatment period (up to Study Week 29)
Population: Intent-to-Treat (ITT) population: all par. randomized to treatment who received at least one dose of study drug in either treatment period. Number of par. represent those with data available at the time point; however, all par. in the ITT population without missing covariate information and with at least one post Baseline measurement are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 3-hours Post-dose FEV1 at Week 12 of Each Treatment Period | -0.007 Liters | Standard Error 0.0159 |
| UMEC 62.5 µg QD | Change From Baseline in 3-hours Post-dose FEV1 at Week 12 of Each Treatment Period | 0.122 Liters | Standard Error 0.0277 |
| UMEC 125 µg QD | Change From Baseline in 3-hours Post-dose FEV1 at Week 12 of Each Treatment Period | 0.156 Liters | Standard Error 0.0275 |
| VI 25 µg QD | Change From Baseline in 3-hours Post-dose FEV1 at Week 12 of Each Treatment Period | 0.115 Liters | Standard Error 0.0229 |
| UMEC/VI 62.5/25 µg QD | Change From Baseline in 3-hours Post-dose FEV1 at Week 12 of Each Treatment Period | 0.254 Liters | Standard Error 0.0166 |
| UMEC/VI 125/25 µg QD | Change From Baseline in 3-hours Post-dose FEV1 at Week 12 of Each Treatment Period | 0.217 Liters | Standard Error 0.0169 |
Secondary
Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period
Functional Residual Capacity (FRC) is defined as the amount of air still left in the lungs after breathing out normally. Baseline is the FRC value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Trough FRC is measured pre-dose on Treatment Week 12. FRC 3-hours post-dose is measured from the value obtained 3 hours after dosing on Treatment Week 12. Analysis performed using a repeated measures model with covariates of period Baseline, mean Baseline, period, treatment, visit, smoking status, center group, visit by period Baseline, visit by mean Baseline and visit by treatment interactions. FRC measurements were taken electronically by plethysmography on Day 2, Week 6 and Week 12.
Time frame: Week 12 of each treatment period (up to Study Week 29)
Population: Intent-to-Treat (ITT) population: all par. randomized to treatment who received at least one dose of study drug in either treatment period. Number of par. represent those with data available at the time point; however, all par. in the ITT population without missing covariate information and with at least one post Baseline measurement are included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | 0.020 Liters | Standard Error 0.0494 |
| Placebo | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.081 Liters | Standard Error 0.0495 |
| UMEC 62.5 µg QD | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.262 Liters | Standard Error 0.0899 |
| UMEC 62.5 µg QD | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.358 Liters | Standard Error 0.0893 |
| UMEC 125 µg QD | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.241 Liters | Standard Error 0.089 |
| UMEC 125 µg QD | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.456 Liters | Standard Error 0.0885 |
| VI 25 µg QD | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.109 Liters | Standard Error 0.0738 |
| VI 25 µg QD | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.229 Liters | Standard Error 0.0734 |
| UMEC/VI 62.5/25 µg QD | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.219 Liters | Standard Error 0.0523 |
| UMEC/VI 62.5/25 µg QD | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.384 Liters | Standard Error 0.0523 |
| UMEC/VI 125/25 µg QD | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.350 Liters | Standard Error 0.0524 |
| UMEC/VI 125/25 µg QD | Change From Baseline in Functional Residual Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.548 Liters | Standard Error 0.0526 |
Secondary
Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period
Inspiratory capacity (IC) is defined as the maximum amount of air that can be inhaled into the lungs from the normal resting position after breathing out normally. Baseline is the IC value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Trough IC is measured pre-dose on Treatment Week 12 of each treatment period. IC 3-hours post-dose is measured from the value obtained 3 hours after dosing on Treatment Week 12 of each treatment period. Analysis performed using a repeated measures model with covariates of period Baseline, mean Baseline, period, treatment, visit, smoking status, center group, visit by period Baseline, visit by mean Baseline and visit by treatment interactions. IC measurements were taken electronically by plethysmography on Day 2, Week 6 and Week 12.
Time frame: Week 12 of each treatment period (up to Study Week 29)
Population: Intent-to-Treat (ITT) population: all par. randomized to treatment who received at least one dose of study drug in either treatment period. Number of par. represent those with data available at the time point; however, all par. in the ITT population without missing covariate information and with at least one post Baseline measurement are included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.002 Liters | Standard Error 0.0255 |
| Placebo | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | 0.028 Liters | Standard Error 0.0259 |
| UMEC 62.5 µg QD | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | 0.025 Liters | Standard Error 0.0457 |
| UMEC 62.5 µg QD | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | 0.142 Liters | Standard Error 0.0463 |
| UMEC 125 µg QD | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | 0.187 Liters | Standard Error 0.0457 |
| UMEC 125 µg QD | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | 0.249 Liters | Standard Error 0.0462 |
| VI 25 µg QD | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | 0.067 Liters | Standard Error 0.0377 |
| VI 25 µg QD | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | 0.160 Liters | Standard Error 0.0382 |
| UMEC/VI 62.5/25 µg QD | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | 0.196 Liters | Standard Error 0.0269 |
| UMEC/VI 62.5/25 µg QD | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | 0.267 Liters | Standard Error 0.0274 |
| UMEC/VI 125/25 µg QD | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | 0.168 Liters | Standard Error 0.027 |
| UMEC/VI 125/25 µg QD | Change From Baseline in Inspiratory Capacity (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | 0.250 Liters | Standard Error 0.0275 |
Secondary
Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period
Residual Volume (RV) is defined as the air that remains in the lungs after breathing out as fully as possible. Baseline is the RV value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each participant. Trough RV is measured pre-dose on Treatment Week 12. RV 3-hours post-dose is measured from the value obtained 3 hours after dosing on Treatment Week 12. Analysis performed using a repeated measures model with covariates of period Baseline, mean Baseline, period, treatment, visit, smoking status, center group, visit by period Baseline, visit by mean Baseline and visit by treatment interactions. RV measurements were taken electronically by plethysmography on Day 2, Week 6 and Week 12.
Time frame: Week 12 of each treatment period (up to Study Week 29)
Population: Intent-to-Treat (ITT) population: all par. randomized to treatment who received at least one dose of study drug in either treatment period. Number of par. represent those with data available at the time point; however, all par. in the ITT population without missing covariate information and with at least one post Baseline measurement are included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | 0.039 Liters | Standard Error 0.0521 |
| Placebo | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.086 Liters | Standard Error 0.0526 |
| UMEC 62.5 µg QD | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.337 Liters | Standard Error 0.0948 |
| UMEC 62.5 µg QD | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.375 Liters | Standard Error 0.0955 |
| UMEC 125 µg QD | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.249 Liters | Standard Error 0.094 |
| UMEC 125 µg QD | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.451 Liters | Standard Error 0.0945 |
| VI 25 µg QD | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.138 Liters | Standard Error 0.0779 |
| VI 25 µg QD | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.253 Liters | Standard Error 0.0784 |
| UMEC/VI 62.5/25 µg QD | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.255 Liters | Standard Error 0.0552 |
| UMEC/VI 62.5/25 µg QD | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.437 Liters | Standard Error 0.0556 |
| UMEC/VI 125/25 µg QD | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | Trough | -0.432 Liters | Standard Error 0.0553 |
| UMEC/VI 125/25 µg QD | Change From Baseline in Residual Volume (Trough and 3-hours Post-dose) at Week 12 of Each Treatment Period | 3-hours post-dose | -0.625 Liters | Standard Error 0.056 |