Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The purpose of the study is to investigate the efficacy and safety of fluticasone furoate/vilanterol Inhalation Powder compared with placebo over a 24 weeks treatment period in subjects of Asian ancestry with Chronic Obstructive Pulmonary Disease (COPD).
Interventions
Inhaled corticosteroid/long acting beta-agonist
DRUGPlacebo
matching placebo
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* COPD diagnosis define by ATS(American Thoracic Society)/ ERS (European Respiratory Society) * Subjects of Asian ancestry * Valid informed consent * Current or former smoker * \> or = 2 on the modified Medical Research Council Dyspnea Scale at Screening
Exclusion criteria
* Pregnancy * A current diagnosis of asthma * alpha1-antitrypsin deficiency as the underlying cause for COPD * Other active, respiratory disorders * Have lung volume reduction surgery within 12 months prior to Screening * A chest X-ray or CT (Computerised Tomography) scan reveals evidence of clinical significant abnormalities not believed to be due to the presence of COPD * Poorly controlled COPD: acute worsening of COPD managed by corticosteroids, antibiotics, or treatments prescribed by a physician 6 weeks prior to Screening, or requires hospitalisation due to poorly controlled COPD 12 weeks prior to Screening * Lower respiratory tract infection requires antibiotics within 4 weeks prior to Screening * Other disease or abnormalities, in the opinion of the investigator, would put the safety of the subject at risk during the study or would affect safety or efficacy analysis if the disease/condition exacerbated during the study * Subject with carcinoma that has not been in complete remission for at least 5 years, carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis. * Subject has a history of hypersensitivity to any of the study medications or components of the inhalation powder. Subject has a history of severe milk protein allergy that, in the opinion of the investigator, contraindicates the subject's participation will also be excluded. * Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years prior to Screening * Subjects who are medically unable to withhold albuterol, ipratropium for 4 hrs and/or theophylline for 12 hrs prior to spirometry testing. * Subjects use a list of prohibited medications specified in the study protocol, including but not limited to traditional or herbal medications for the treatment of COPD * Subject requires long-term oxygen therapy or nocturnal oxygen therapy for greater than 12 hours a day * Pulmonary rehabilitation: subjects who are in the maintenance phase are not excluded. * Non-compliance * Questionable validity of the Informed Consent * Prior use of study medication or other investigational drugs * Affiliation with investigator site
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Clinic Visit Pre-dose Trough FEV1 at Day 169 | Baseline to Day 169 | Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 was defined as the pre-dose and pre-bronchodilator FEV1, which was obtained at each clinic visit. Baseline is defined as the mean of the two 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 23 and 24 hours after dosing at each clinic visit. Change from Baseline was calculated as the average at each clinic visit minus the Baseline value. Analysis was performed using a repeated measures model with covariates of treatment, smoking status at screening (stratum), baseline - mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Day 1, day, day by baseline and day by treatment interactions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Domain Score at Day 168 | Baseline (BL) and Day 168 | CRQ-SAS measures 4 domains (fatigue, emotional function, mastery and dyspnea) of functioning of participants (par.) with COPD: mastery (amount of control the par. feels he/she has over COPD symptoms); fatigue (how tired the par. feels); emotional function (how anxious/depressed the par. feels); and dyspnea (how short of breath the par. feels during physical activities). Each domain is calculated separately and measured on a scale of 1-7 (1=maximum impairment; 7=no impairment). Dyspnea domain score is the mean of all non-missing responses for that domain. Only the dyspnea domain was measured as a secondary outcome. BL scores are the derived scores for each domain and total at Day 1 pre-dose. Change from BL was calculated as the average of the Day 168 values minus the BL value. Analysis performed used a repeated measures model with covariates of treatment, smoking status at screening (stratum), BL (derived scores at Day 1 pre-dose), day, day by BL, and day by treatment interactions. |
Countries
China, Philippines, South Korea, Taiwan
Participant flow
Pre-assignment details
Eligible participants (par.) completed a 2-week Run-in Period for symptom scores at baseline and to establish a stable baseline. Par. were then randomized to a 24-week (wk) Treatment Period. 880 par. were screened, 744 entered the RIP and 646 par were randomized, out of which 643 par received \>=1 study treatment dose.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo once daily (OD) in the morning for 24 weeks. In addition, participants were provided supplemental albuterol/salbutamol (metered dose inhaler \[MDI\] or nebules) to be used as needed throughout the study. | 162 |
| FF /VI 50/25 µg OD Participants received Fluticasone Furoate (FF)/Vilanterol (VI) 50/25 micrograms (µg) OD in the morning over the 24-week treatment period. In addition, participants were provided albuterol/salbutamol (MDI or nebules) to be used as needed throughout the study. | 160 |
| FF/VI 100/25 µg OD Participants received FF/VI 100/25 µg OD in the morning over the 24-week treatment period. In addition, participants were provided albuterol/salbutamol (MDI or nebules) to be used as needed throughout the study. | 161 |
| FF/VI 200/25 µg OD Participants received FF/VI 200/25 µg OD in the morning over the 24-week treatment period. In addition, participants were provided albuterol/salbutamol (MDI or nebules) to be used as needed throughout the study. | 160 |
| Total | 643 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| 24-week, Double-blind Treatment Period | Adverse Event | 0 | 16 | 7 | 8 | 18 |
| 24-week, Double-blind Treatment Period | Lack of Efficacy | 0 | 4 | 5 | 4 | 3 |
| 24-week, Double-blind Treatment Period | Lost to Follow-up | 0 | 2 | 0 | 1 | 1 |
| 24-week, Double-blind Treatment Period | Met Protocol-Defined Stopping Criteria | 0 | 2 | 3 | 1 | 0 |
| 24-week, Double-blind Treatment Period | Physician Decision | 0 | 0 | 1 | 1 | 0 |
| 24-week, Double-blind Treatment Period | Protocol Violation | 0 | 2 | 0 | 2 | 1 |
| 24-week, Double-blind Treatment Period | Withdrawal by Subject | 0 | 6 | 9 | 6 | 3 |
| 2-wk Single-blind Placebo Run-in Period | Adverse Event | 4 | 0 | 0 | 0 | 0 |
| 2-wk Single-blind Placebo Run-in Period | Did Not Meet Continuation Criteria | 66 | 0 | 0 | 0 | 0 |
| 2-wk Single-blind Placebo Run-in Period | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| 2-wk Single-blind Placebo Run-in Period | Physician Decision | 2 | 0 | 0 | 0 | 0 |
| 2-wk Single-blind Placebo Run-in Period | Withdrawal by Subject | 28 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | FF /VI 50/25 µg OD | FF/VI 100/25 µg OD | FF/VI 200/25 µg OD | Total |
|---|---|---|---|---|---|
| Age, Continuous | 64.7 Years STANDARD_DEVIATION 8.78 | 65.2 Years STANDARD_DEVIATION 8.41 | 65.1 Years STANDARD_DEVIATION 9.19 | 62.7 Years STANDARD_DEVIATION 8.65 | 64.4 Years STANDARD_DEVIATION 8.8 |
| Gender Female | 16 Participants | 16 Participants | 12 Participants | 15 Participants | 59 Participants |
| Gender Male | 146 Participants | 144 Participants | 149 Participants | 145 Participants | 584 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 151 Participants | 149 Participants | 150 Participants | 148 Participants | 598 Participants |
| Race/Ethnicity, Customized Asian - South East Asian | 11 Participants | 11 Participants | 11 Participants | 12 Participants | 45 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 | 27 / 162 | 33 / 160 | 34 / 161 | 40 / 160 |
| serious Total, serious adverse events | 14 / 162 | 9 / 160 | 7 / 161 | 14 / 160 |
Outcome results
Primary
Mean Change From Baseline in Clinic Visit Pre-dose Trough FEV1 at Day 169
Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 was defined as the pre-dose and pre-bronchodilator FEV1, which was obtained at each clinic visit. Baseline is defined as the mean of the two 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 23 and 24 hours after dosing at each clinic visit. Change from Baseline was calculated as the average at each clinic visit minus the Baseline value. Analysis was performed using a repeated measures model with covariates of treatment, smoking status at screening (stratum), baseline - mean of the two assessments made 30 minutes pre-dose and immediately pre-dose on Day 1, day, day by baseline and day by treatment interactions.
Time frame: Baseline to Day 169
Population: Intent-to-Treat (ITT) Population: all randomized par. who received at least one dose of study medication. Number of par. presented represents those with data available at the time point being presented, however, all par. in the ITT population without missing covariate information with at least one post BL measurement are included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in Clinic Visit Pre-dose Trough FEV1 at Day 169 | -0.027 Liters | Standard Error 0.0184 |
| FF/VI 50/25 µg OD | Mean Change From Baseline in Clinic Visit Pre-dose Trough FEV1 at Day 169 | 0.113 Liters | Standard Error 0.0183 |
| FF/VI 100/25 µg OD | Mean Change From Baseline in Clinic Visit Pre-dose Trough FEV1 at Day 169 | 0.152 Liters | Standard Error 0.0181 |
| FF/VI 200/25 µg OD | Mean Change From Baseline in Clinic Visit Pre-dose Trough FEV1 at Day 169 | 0.167 Liters | Standard Error 0.0182 |
p-value: <0.00195% CI: [0.129, 0.23]Mixed Models Analysis
p-value: <0.00195% CI: [0.089, 0.191]Mixed Models Analysis
p-value: <0.00195% CI: [0.143, 0.245]Mixed Models Analysis
Secondary
Mean Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Domain Score at Day 168
CRQ-SAS measures 4 domains (fatigue, emotional function, mastery and dyspnea) of functioning of participants (par.) with COPD: mastery (amount of control the par. feels he/she has over COPD symptoms); fatigue (how tired the par. feels); emotional function (how anxious/depressed the par. feels); and dyspnea (how short of breath the par. feels during physical activities). Each domain is calculated separately and measured on a scale of 1-7 (1=maximum impairment; 7=no impairment). Dyspnea domain score is the mean of all non-missing responses for that domain. Only the dyspnea domain was measured as a secondary outcome. BL scores are the derived scores for each domain and total at Day 1 pre-dose. Change from BL was calculated as the average of the Day 168 values minus the BL value. Analysis performed used a repeated measures model with covariates of treatment, smoking status at screening (stratum), BL (derived scores at Day 1 pre-dose), day, day by BL, and day by treatment interactions.
Time frame: Baseline (BL) and Day 168
Population: ITT Population. Only those participants available at the indicated time point were assessed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Domain Score at Day 168 | 0.09 Scores on a scale | Standard Error 0.081 |
| FF/VI 50/25 µg OD | Mean Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Domain Score at Day 168 | 0.30 Scores on a scale | Standard Error 0.08 |
| FF/VI 100/25 µg OD | Mean Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Domain Score at Day 168 | 0.43 Scores on a scale | Standard Error 0.079 |
| FF/VI 200/25 µg OD | Mean Change From Baseline in Chronic Respiratory Disease Questionnaire Self-administered Standardized (CRQ-SAS) Dyspnea Domain Score at Day 168 | 0.37 Scores on a scale | Standard Error 0.08 |