Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The purpose of this study is to evaluate the 24-hour spirometry effect (FEV1) of FF/VI 100/25mcg once daily compared with Fluticasone Propionate/Salmeterol 250/50mcg twice daily over a 12-week treatment period in subjects with COPD.
Detailed description
This is a randomized, double-blind, double-dummy, multi-centre parallel group study. Subjects who meet the eligibility criteria at Screening and meet the randomization criteria at the end of a 2-week Run-In period will enter a 12-week treatment period. There will be a 7-day Follow-up period after the treatment period.
Interventions
DRUGFluticasone Furoate 100mcg/ GW642444 (vilanterol) 25mcg
inhalation powder
DRUGFluticasone Propionate 250mcg / salmeterol 50mcg
inhalation powder
DRUGDouble-dummy placebo
inhalation powder
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
* Signed and dated written informed consent * Male or females ≥ 40 years of age * Established clinical history of COPD by ATS/ERS definition * Females are eligible to enter and participate if of non-childbearing potential, or if of child bearing potential, has a negative serum pregnancy test at screening, and agrees to one of the acceptable contraceptive methods listed in protocol, used consistently and correctly * Former or current smoker \> 10 pack years * Post-albuterol spirometry criteria: FEV1/FVC ratio ≤ 0.70 and FEV1 ≤ 70% of predicted normal (NHANES III)
Exclusion criteria
* Current diagnosis of asthma * Subjects with other respiratory disorders including active tuberculosis, α1-antitrypsin deficiency, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases * Lung volume reduction surgery within previous 12 months * Clinically significant abnormalities not due to COPD by chest x-ray * Hospitalized for poorly controlled COPD within 12 weeks of Screening * Poorly controlled COPD 6 weeks prior to Screening, defined as acute worsening of COPD that is managed by the subject with corticosteroids or antibiotics or that requires treatment prescribed by a physician * Lower respiratory infection requiring antibiotics 6 weeks prior to Screening * Uncontrolled or clinically significant (in opinion of PI) cardiovascular, hypertension, neurological, psychiatric, renal, hepatic, immunological, endocrine, peptic ulcer disease, or hematological abnormalities * Carcinoma not in complete remission for at least 5 years * Subjects with history of hypersensitivity to study medications (e.g., beta-agonists, corticosteroid) or components of inhalation powder (e.g., lactose, magnesium stearate) * Subjects with history of severe milk protein allergy that, in opinion of study physician, contraindicates subject's participation * Known/suspected history of alcohol or drug abuse in the last 2 years * Women who are pregnant or lactating or plan to become pregnant * Subjects medically unable to withhold albuterol and/or ipratropium 4 hours prior to spirometry testing at each study visit * Use of certain medications such as bronchodilators and corticosteroids for the protocol-specific times prior to Visit 1 (the Investigator will discuss the specific medications) * Long Term Oxygen Therapy (LTOT) or nocturnal oxygen therapy \>12 hours a day * Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Screening or during the study * Non-compliance or inability to comply with study procedures or scheduled visits * Affiliation with investigator site
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Trough in 24-Hour Weighted Mean FEV1 on Treatment Day 84 | Baseline (Day 1) and Day 84 | 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. The weighted mean was calculated from the pre-dose FEV1 and the post-dose FEV1 measurements at 5, 15, 30, and 60 minutes (min) and 2, 4, 6, 8, 12, 13, 14, 16, 20, and 24 hours post-dose on Treatment Day 84. Baseline trough FEV1 was calculated as the mean of the two assessments made 30 and 5 minutes pre-dose on Treatment Day 1. Change from Baseline was calculated as the average of the Day 84 values minus the Baseline value. Analysis of covariance (ANCOVA) was conducted with covariates for country, smoking status, reversibility, and Baseline FEV1. |
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. Time to onset was calculated over 0 to 4 hours (5 min, 15 min, 30 min, 60 min, 120 min, and 240 min) post-dose. |
Countries
Germany, Italy, South Africa, Spain, Ukraine, United States
Participant flow
Pre-assignment details
At Visit 1, eligible participants entered a 2-week, single blind (placebo) Run-In Period to obtain Baseline assessments of albuterol (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 Treatment Period.
Participants by arm
| Arm | Count |
|---|---|
| FSC 250/50 µg BID Participants received a Fluticasone Propionate and Salmeterol (FSC) 250/50 microgram (µg) inhalation (available as a combination dry inhalation powder of Fluticasone 250 µg and Salmeterol 50 µg in a single strip) twice daily (BID) (morning and evening) from the ACCUHALER/DISKUS and placebo once daily (QD) in the morning from the NDPI over the course of 12 weeks. | 252 |
| FF/VI 100/25 µg QD Participants received a Fluticasone Furoate /Vilanterol (FF/VI) 100/25 µg inhalation (available as a dry inhalation powder in two separate strips of FF 100 µg and VI 25 µg) QD in the morning from the NDPI and placebo BID (morning and evening) from the ACCUHALER/DISKUS over the course of 12 weeks. | 259 |
| Total | 511 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 12-week, Double-blind Treatment Period | Adverse Event | 0 | 1 | 5 |
| 12-week, Double-blind Treatment Period | Lack of Efficacy | 0 | 2 | 6 |
| 12-week, Double-blind Treatment Period | Lost to Follow-up | 0 | 1 | 0 |
| 12-week, Double-blind Treatment Period | Physician Decision | 0 | 2 | 1 |
| 12-week, Double-blind Treatment Period | Protocol Violation | 0 | 4 | 4 |
| 12-week, Double-blind Treatment Period | Withdrawal by Subject | 0 | 5 | 4 |
| 2-week, Single-blind Run In Period | Did Not Meet Continuation Criteria | 86 | 0 | 0 |
| 2-week, Single-blind Run In Period | Lost to Follow-up | 1 | 0 | 0 |
| 2-week, Single-blind Run In Period | Not Met Inclusion/Exclusion Criteria | 121 | 0 | 0 |
| 2-week, Single-blind Run In Period | Physician Decision | 7 | 0 | 0 |
| 2-week, Single-blind Run In Period | Protocol Violation | 1 | 0 | 0 |
| 2-week, Single-blind Run In Period | Withdrawal by Subject | 12 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | FF/VI 100/25 µg QD | FSC 250/50 µg BID |
|---|---|---|---|
| Age, Continuous | 61.6 Years STANDARD_DEVIATION 9.32 | 61.6 Years STANDARD_DEVIATION 9.59 | 61.7 Years STANDARD_DEVIATION 9.05 |
| Race/Ethnicity, Customized African American/African Heritage | 31 participants | 17 participants | 14 participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 479 participants | 241 participants | 238 participants |
| Sex: Female, Male Female | 163 Participants | 78 Participants | 85 Participants |
| Sex: Female, Male Male | 348 Participants | 181 Participants | 167 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 252 | 12 / 259 |
| serious Total, serious adverse events | 3 / 252 | 5 / 259 |
Outcome results
Primary
Change From Baseline Trough in 24-Hour Weighted Mean FEV1 on Treatment Day 84
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. The weighted mean was calculated from the pre-dose FEV1 and the post-dose FEV1 measurements at 5, 15, 30, and 60 minutes (min) and 2, 4, 6, 8, 12, 13, 14, 16, 20, and 24 hours post-dose on Treatment Day 84. Baseline trough FEV1 was calculated as the mean of the two assessments made 30 and 5 minutes pre-dose on Treatment Day 1. Change from Baseline was calculated as the average of the Day 84 values minus the Baseline value. Analysis of covariance (ANCOVA) was conducted with covariates for country, smoking status, reversibility, and Baseline FEV1.
Time frame: Baseline (Day 1) and Day 84
Population: Intent-to-Treat (ITT) Population: all participants randomized to treatment who received at least one dose of study drug. Only those participants available at the indicated time points were assessed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FSC 250/50 µg BID | Change From Baseline Trough in 24-Hour Weighted Mean FEV1 on Treatment Day 84 | 0.114 Liters | Standard Error 0.0183 |
| FF/VI 100/25 µg QD | Change From Baseline Trough in 24-Hour Weighted Mean FEV1 on Treatment Day 84 | 0.142 Liters | Standard Error 0.0182 |
p-value: 0.26795% CI: [-0.022, 0.08]ANCOVA
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. Time to onset was calculated over 0 to 4 hours (5 min, 15 min, 30 min, 60 min, 120 min, and 240 min) post-dose.
Time frame: Baseline and Day 1
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FSC 250/50 µg BID | Time to Onset on Treatment Day 1 | 30 Minutes |
| FF/VI 100/25 µg QD | Time to Onset on Treatment Day 1 | 16 Minutes |