Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Vilanterol (VI), Novel Dry Powder Inhaler (NDPI), FEV1, Fluticasone Furoate (FF), COPD
Brief summary
This will be a Phase IIIb multicentre, randomized, double-blind, double-dummy, 12-week parallel group study evaluating the effects of once daily in the morning treatment of FF/VI Inhalation Powder versus Fluticasone Propionate/Salmeterol Inhalation Powder twice daily on lung function in COPD subjects. Subjects will be screened and will enter a 2-week, single-blind (placebo), Run-In Period to evaluate the subject's adherence with study treatment, study procedures and assessment of disease stability. At the end of the Run-In Period, subjects will return to the Clinic and who meet all of the Randomization Criteria will be randomized to double-blind study medication (12-week treatment period). Subjects will be randomized to receive either FF/VI 100/25 via NDPI or Fluticasone Propionate/Salmeterol 250/50mcg via ACCUHALER/DISKUS. Matching placebos will be available in NDPI and ACCUHALER/DISKUS. Each morning (approximately 6-10 AM) subjects will take 1 inhalation from the NDPI followed by 1 inhalation from the ACCUHALER/DISKUS. Each evening (approximately 6-10 PM), approximately 12 hours after the morning dose with blinded study medication, subjects will take 1 inhalation from the ACCUHALER/DISKUS. Subjects will return to the clinic at the end of the treatment period. A follow-up phone contact will be performed approximately 7 days after the last clinic visit. The overall study duration (Screening to Follow-up) for each subject is approximately 15 weeks.
Interventions
DRUGFF/VI 100/25 Inhalation Powder NDPI
Subjects randomized to the FF/VI Inhalation Powder Novel Dry Powder Inhaler (NDPI) arm will receive a single inhalation of 100 mcg FF and 25 mcg VI via NDPI every morning for 12 weeks.
DRUGFluticasone Propionate/Salmeterol 250/50 Inhalation Powder ACCUHALER/DISKUS
Subjects randomized to the Fluticasone Propionate/Salmeterol Inhalation Powder ACCUHALER/DISKUS arm will receive a single inhalation of 250 mcg Fluticasone Propionate and 50 mcg Salmeterol via ACCUHALER/DISKUS once in the morning and once in the evening for 12 weeks.
Subjects randomized to the Fluticasone Propionate/Salmeterol Inhalation Powder ACCUHALER/DISKUS arm will receive a single inhalation of placebo inhalation powder via NDPI every morning for 12 weeks.
DRUGPlacebo Inhalation Powder ACCUHALER/DISKUS
Subjects randomized to the FF/VI Inhalation Powder NDPI arm will receive a single inhalation of placebo inhalation powder via ACCUHALER/DISKUS once in the morning and once in the evening for 12 weeks.
Salbutamol inhalation powder
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
* A male or female \>=40 years of age at Screening (Visit 1). * Capable of giving written informed consent. * Female subjects must be post-menopausal or using a highly effective method for avoidance of pregnancy. * Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society/European Respiratory Society. * Subject with a measured post-albuterol (salbutamol) FEV1/forced vital capacity(FVC) ratio of \<=0.70 at Screening. * Subjects with a measured post-albuterol (salbutamol) FEV1 \<=70% of predicted normal values. * Subjects with a current or prior history of ≥10 pack-years of cigarette smoking at Screening.
Exclusion criteria
* Current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD). * Other respiratory disorders (alpha1-antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, pulmonary fibrosis, pulmonary hypertension, interstitial lung diseases, or other active pulmonary diseases). * Lung volume reduction surgery within the 12 months prior to Screening. * Hospitalized due to poorly controlled COPD within 12 weeks of Screening. * Poorly controlled COPD (occurrence of the following in the 6 weeks prior to Screening -Acute worsening of COPD that is managed by the subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician). * Lower respiratory tract infection that required the use of antibiotics within 6 weeks prior to Screening. * Moderate/severe COPD exacerbation/lower respiratory tract infection during Run-In Period. * Abnormal and clinically significant 12-lead ECG at Screening * Historical or current evidence of uncontrolled or clinically significant disease like cardiovascular, hypertension, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease), peptic ulcer disease, or haematological abnormalities. 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. * History of hypersensitivity to any of the study medications or components of the inhalation powder; or history of severe milk protein allergy. * Known or suspected history of alcohol or drug abuse within the last 2 years. * Subjects who are medically unable to withhold their albuterol (salbutamol) and/or their ipratropium for the 4-hour period required prior to spirometry testing at each study visit. * The subject has taken any other investigational drug within 30 days or 5 half-lives of the investigational product (IP) prior to the first dosing day in the current study. * Use of additional medications prior to Screening (list of medications and time intervals are different for different class of medications and are indicated in the protocol) * Subjects receiving treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use (i.e., \<=12 hours per day) is not exclusionary. * Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Screening * Subjects at risk of non-compliance, or unable to comply with study procedures. * Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study. * Women who are pregnant or lactating or are planning on becoming pregnant during the study. * Previously randomized to either the HZC113109 or HZC112352 clinical studies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Trough in Weighted-mean 24-hour Serial Forced Expiratory Volume in One Second (FEV1) on Treatment Day 84 | Baseline and Day 84 | FEV1 is a measure of lung function and is defined as the volume of air that can be forcefully exhaled in one second. The weighted mean was calculated from the pre-dose FEV1 and the post-dose FEV1 measurements taken at 5, 15, 30, and 60 minutes and 2, 4, 6, 8, 12, 13, 14, 16, 20, and 24 hours on Treatment Day 84. Baseline trough FEV1 was calculated as the mean of the two assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. The weighted mean was derived by calculating the area under curve, and then dividing by the relevant time interval. The weighted mean change from Baseline was calculated as the weighted mean of the 24-hour serial FEV1 measurements on Day 84 minus the Baseline trough FEV1 value. The analysis used an analysis of covariance (ANCOVA) model with covariates of Baseline FEV1, reversibility stratum, smoking status (at Screening), country, and treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset on Treatment Day 1 | Baseline and Day 1 | Time to onset on Treatment Day 1 is defined as the time to an increase of 100 milliliters (mL) from Baseline in FEV1 during the 0- to 4-hour serial measurements (5, 15, 30, 60, 120, and 240 minutes post-dose). Participants who never met or exceeded a 100 mL increase over the Baseline value during the 4-hour serial measurements were censored at the actual time of their last FEV1 measurement. |
| Change From Baseline in Trough FEV1 on Treatment Day 85 | Baseline and Day 85 | FEV1 is a measure of lung function and is defined as the volume of air that can be forcefully exhaled in one second. Trough FEV1 is defined as the 24-hour FEV1 assessment, which was obtained on Day 85. Baseline trough was calculated as the mean of the two assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Change from Baseline was calculated as the average of the Day 85 values minus the Baseline value. The analysis used an analysis of covariance (ANCOVA) model with covariates of Baseline FEV1, reversibility stratum, smoking status (at Screening), country, and treatment. |
Countries
Germany, Romania, Russia, Ukraine, United States
Participant flow
Recruitment details
Only those participants that started the Double-blind Treatment Period were considered enrolled.
Pre-assignment details
At Visit 1, participants entered a 2-week, single-blind (placebo) Run-in Period to obtain Baseline assessments of salbutamol use and to evaluate adherence with study treatment and procedures, diary card completion, and assessment of disease stability. At Visit 2, participants were randomized to a 12-week, double-blind Treatment Period.
Participants by arm
| Arm | Count |
|---|---|
| FF/VI 100/25 µg QD Participants received one inhalation of fluticasone furoate/vilanterol (FF/VI) 100/25 micrograms (µg) once daily (QD) in the morning from a DPI and placebo twice daily (BID) from a DPI (one inhalation in the morning and one inhalation in the evening) for 12 weeks. In addition, participants were provided supplemental albuterol (salbutamol) inhalation to be used as needed throughout the study. | 412 |
| FP/Salmeterol 250/50 µg BID Participants received fluticasone propionate (FP)/salmeterol 250/50 µg BID from a DPI (one inhalation in the morning and one inhalation in the evening) plus placebo QD in the morning from a DPI for 12 weeks. In addition, participants were provided supplemental albuterol (salbutamol) to be used as needed throughout the study. | 416 |
| Total | 828 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 12-week Double-blind Treatment Period | Adverse Event | 0 | 14 | 16 |
| 12-week Double-blind Treatment Period | Lack of Efficacy | 0 | 4 | 4 |
| 12-week Double-blind Treatment Period | Lost to Follow-up | 0 | 3 | 1 |
| 12-week Double-blind Treatment Period | Physician Decision | 0 | 2 | 2 |
| 12-week Double-blind Treatment Period | Protocol-defined Stopping Criteria Met | 0 | 11 | 9 |
| 12-week Double-blind Treatment Period | Protocol Violation | 0 | 4 | 2 |
| 12-week Double-blind Treatment Period | Withdrawal by Subject | 0 | 8 | 11 |
| 2-week Run-in Period | Adverse Event | 4 | 0 | 0 |
| 2-week Run-in Period | Inclusion/Exclusion Criteria Not Met | 140 | 0 | 0 |
| 2-week Run-in Period | Lost to Follow-up | 2 | 0 | 0 |
| 2-week Run-in Period | Physician Decision | 4 | 0 | 0 |
| 2-week Run-in Period | Withdrawal by Subject | 15 | 0 | 0 |
Baseline characteristics
| Characteristic | FF/VI 100/25 µg QD | FP/Salmeterol 250/50 µg BID | Total |
|---|---|---|---|
| Age, Continuous | 61.0 Years STANDARD_DEVIATION 8.17 | 61.3 Years STANDARD_DEVIATION 8.37 | 61.1 Years STANDARD_DEVIATION 8.27 |
| Race/Ethnicity, Customized African American/African Heritage | 9 participants | 5 participants | 14 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White-White/Caucasian/European Heritage | 403 participants | 410 participants | 813 participants |
| Sex: Female, Male Female | 111 Participants | 122 Participants | 233 Participants |
| Sex: Female, Male Male | 301 Participants | 294 Participants | 595 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 412 | 52 / 416 |
| serious Total, serious adverse events | 13 / 412 | 20 / 416 |
Outcome results
Primary
Change From Baseline Trough in Weighted-mean 24-hour Serial Forced Expiratory Volume in One Second (FEV1) on Treatment Day 84
FEV1 is a measure of lung function and is defined as the volume of air that can be forcefully exhaled in one second. The weighted mean was calculated from the pre-dose FEV1 and the post-dose FEV1 measurements taken at 5, 15, 30, and 60 minutes and 2, 4, 6, 8, 12, 13, 14, 16, 20, and 24 hours on Treatment Day 84. Baseline trough FEV1 was calculated as the mean of the two assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. The weighted mean was derived by calculating the area under curve, and then dividing by the relevant time interval. The weighted mean change from Baseline was calculated as the weighted mean of the 24-hour serial FEV1 measurements on Day 84 minus the Baseline trough FEV1 value. The analysis used an analysis of covariance (ANCOVA) model with covariates of Baseline FEV1, reversibility stratum, smoking status (at Screening), country, and treatment.
Time frame: Baseline and Day 84
Population: Intent-to-Treat (ITT) Population: all participants who were randomized and received at least one dose of study drug. Only those participants available at the indicated time point were assessed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF/VI 100/25 µg QD | Change From Baseline Trough in Weighted-mean 24-hour Serial Forced Expiratory Volume in One Second (FEV1) on Treatment Day 84 | 0.168 Liters | Standard Error 0.0121 |
| FP/Salmeterol 250/50 µg BID | Change From Baseline Trough in Weighted-mean 24-hour Serial Forced Expiratory Volume in One Second (FEV1) on Treatment Day 84 | 0.142 Liters | Standard Error 0.012 |
p-value: 0.13795% CI: [-0.008, 0.059]ANCOVA
Secondary
Change From Baseline in Trough FEV1 on Treatment Day 85
FEV1 is a measure of lung function and is defined as the volume of air that can be forcefully exhaled in one second. Trough FEV1 is defined as the 24-hour FEV1 assessment, which was obtained on Day 85. Baseline trough was calculated as the mean of the two assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Change from Baseline was calculated as the average of the Day 85 values minus the Baseline value. The analysis used an analysis of covariance (ANCOVA) model with covariates of Baseline FEV1, reversibility stratum, smoking status (at Screening), country, and treatment.
Time frame: Baseline and Day 85
Population: ITT Population. Only those participants available at the indicated time point were assessed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF/VI 100/25 µg QD | Change From Baseline in Trough FEV1 on Treatment Day 85 | 0.151 Liters | Standard Error 0.0126 |
| FP/Salmeterol 250/50 µg BID | Change From Baseline in Trough FEV1 on Treatment Day 85 | 0.121 Liters | Standard Error 0.0125 |
Secondary
Time to Onset on Treatment Day 1
Time to onset on Treatment Day 1 is defined as the time to an increase of 100 milliliters (mL) from Baseline in FEV1 during the 0- to 4-hour serial measurements (5, 15, 30, 60, 120, and 240 minutes post-dose). Participants who never met or exceeded a 100 mL increase over the Baseline value during the 4-hour serial measurements were censored at the actual time of their last FEV1 measurement.
Time frame: Baseline and Day 1
Population: ITT Population. Only those participants available at the indicated time point were assessed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FF/VI 100/25 µg QD | Time to Onset on Treatment Day 1 | 15 Minutes |
| FP/Salmeterol 250/50 µg BID | Time to Onset on Treatment Day 1 | 15 Minutes |