Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Cardiovascular event, Cardiovascular disease
Brief summary
The purpose of this study is to evaluate the 24-hour spirometry effect (FEV1) of Fluticasone Furoate/Vilanterol Inhalation Powder 100/25mcg once daily compared with tiotropium bromide inhalation powder 18mcg once daily over a 12-week treatment period in subjects with COPD who have or are at risk for co-morbid cardiovascular disease
Detailed description
This is a randomized, double-blind, double-dummy, multi-center, parallel-group study. Subjects who meet the eligibility criteria at Screening and 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/vilanterol 100/25mcg
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 * Females must be post-menopausal or using a highly effective method for avoidance of pregnancy * Established clinical history of COPD by ATS/ERS definition * Post-albuterol spirometry criteria: FEV1/FVC ratio ≤ 0.70 and FEV1 ≥30 to ≤ 70% of predicted normal (NHANES III) * Former or current smoker ≥10 pack years * A history of diagnosed cardiovascular disease or a prior cardiovascular event including any of the following: * Established (i.e., by clinical signs or imaging studies) coronary artery disease (CAD) * Established (i.e., by clinical signs or imaging studies) peripheral vascular (i.e., arterial) disease (PVD) * Previous stroke * Objectively confirmed transient ischemic attack (TIA) (i.e., transient neurological deficit documented by a health-care professional) * Previous myocardial infarction (MI) (Note: An MI within 6 months prior to Visit 1 is exclusionary) OR * Presence of one of the following cardiovascular risk factors (in addition to being a former/current smoker): * Current diagnosis of hypertension * Current diagnosis of hypercholesterolemia * Diabetes mellitus treated with pharmacotherapy
Exclusion criteria
* Current diagnosis of asthma * Subjects with other respiratory disorders including α1-antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, bronchiectasis (Note: focal bronchiectasis is not exclusionary), sarcoidosis, pulmonary fibrosis (Note: focal fibrotic pulmonary lesions are not exclusionary), 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 or CT scan * 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 * A moderate or severe COPD exacerbation and/or a lower respiratory tract infection (including pnuemonia) during the Run-In Period * An abnormal, clinically significant finding in any liver chemistry, biochemical, or haematology tests at Screening (Visit 1) or upon repeat prior to randomization * An abnormal, clinically significant ECG finding at Screening (Visit 1) or upon repeat prior to randomization * An abnormal, clinically significant Holter finding at Screening (Visit 1) or upon repeat prior to randomization (sub-set of subjects) * Historical or current evidence of clinically significant (in opinion of the Investigator) and unstable disease such as cardiovascular (e.g., patients requiring ICD, pacemaker requiring a ventricular pace rate set at \>60 bpm, uncontrolled hypertension, New York Heart Association Class IV (New York Heart Association,1994), known left ventricular ejection fraction \<30%), neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease), peptic ulcer disease, or haematological abnormalities * Carcinoma not in complete remission for at least 5 years * History of allergy or hypersensitivity to any of the study medications (e.g., anticholinergic/muscarinic receptor antagonist, beta2-agonist, corticosteroid) or components of the inhalation powder (e.g., lactose, 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. In addition, subjects with a history of severe milk protein allergy that, in the opinion of the Investigator, contraindicates the subject's participation will also be excluded * 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 /salbutamol for 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 * Failure to demonstrate adequate compliance defined as completion of the Diary Card (completed all diary entries on at least 4 of the last 7 consecutive days), the ability to withhold COPD medications and to keep clinic visit appointments * Non-compliance or inability to comply with study procedures or scheduled visits * History of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study * Affiliation with investigator site * Women who are pregnant or lactating or are planning on becoming pregnant during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Trough in 24-hour Weighted Mean FEV1 on Treatment Day 84 | Baseline 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 from the lungs in one second. The weighted mean was calculated from the pre-dose FEV1 and post-dose FEV1 measurements at 5, 15, 30 minutes and 1, 2, 4, 6, 8, 12, 13, 14, 16, 20, and 24 hours on Treatment Day 84. Baseline trough FEV1 was the mean of the two assessments made 30 and 5 minutes pre-dose on Treatment Day 1. Change from Baseline (BL) was calculated as the average of the Day 84 values minus the Baseline value. Analysis was performed using an analysis of covariance (ANCOVA) model with covariates of BL FEV1, exacerbation history and reversibility stratum, smoking status at screening, country, and treatment group. |
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 of onset was calculated over 0 to 4 hours (5 minutes (min), 15 min, 30 min, 60 min, 120 min, and 240 min) post-dose. Time to onset was analyzed using a log-rank test, stratified by exacerbation history and reversibility stratum. |
| Change From Baseline in Trough FEV1 at Treatment Day 84 | Baseline and Day 84 | Pulmonary function was measured by FEV1. Trough FEV1 was defined as the 24-hour FEV1 assessment, which was obtained on Day 84. Baseline is defined 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 84 values minus the Baseline value. Analysis was performed using an ANCOVA model with covariates of BL FEV1, exacerbation history and reversibility stratum, smoking status at screening, country, and treatment group. |
Countries
Canada, Czechia, Germany, Poland, Romania, United States
Participant flow
Pre-assignment details
Eligible participants (par.) completed a 2-week Run-in Period (RIP) to obtain baseline assessments of rescue use, COPD symptom scores and disease stability. Par. were then randomized to a 12-week Treatment Period. A total of 890 par. were screened, of whom 623 were randomized and received at least one dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| FF/VI 100/25 µg OD Participants received FF/VI 100/25 µg inhalation OD via a DPI and placebo inhalation OD via a HandiHaler in the morning for 12 weeks. | 310 |
| TIO 18 µg OD Participants received TIO 18 µg inhalation OD via a HandiHaler and placebo inhalation OD via a DPI in the morning for 12 weeks. | 313 |
| Total | 623 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 12 |
| Overall Study | Lack of Efficacy-No Sub-Reason | 0 | 2 |
| Overall Study | Lack of Efficacy-Sub-Reason Exacerbation | 4 | 9 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 4 | 10 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | FF/VI 100/25 µg OD | TIO 18 µg OD | Total |
|---|---|---|---|
| Age, Continuous | 62.9 Years STANDARD_DEVIATION 8.09 | 62.3 Years STANDARD_DEVIATION 7.98 | 62.6 Years STANDARD_DEVIATION 8.03 |
| Race/Ethnicity, Customized African American/African Heritage | 8 Participants | 7 Participants | 15 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 302 Participants | 305 Participants | 607 Participants |
| Sex: Female, Male Female | 117 Participants | 104 Participants | 221 Participants |
| Sex: Female, Male Male | 193 Participants | 209 Participants | 402 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 310 | 32 / 313 |
| serious Total, serious adverse events | 10 / 310 | 10 / 313 |
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 from the lungs in one second. The weighted mean was calculated from the pre-dose FEV1 and post-dose FEV1 measurements at 5, 15, 30 minutes and 1, 2, 4, 6, 8, 12, 13, 14, 16, 20, and 24 hours on Treatment Day 84. Baseline trough FEV1 was the mean of the two assessments made 30 and 5 minutes pre-dose on Treatment Day 1. Change from Baseline (BL) was calculated as the average of the Day 84 values minus the Baseline value. Analysis was performed using an analysis of covariance (ANCOVA) model with covariates of BL FEV1, exacerbation history and reversibility stratum, smoking status at screening, country, and treatment group.
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 medication. Only participants with data available at the indicated time point were assessed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF/VI 100/25 µg OD | Change From Baseline Trough in 24-hour Weighted Mean FEV1 on Treatment Day 84 | 0.117 Liters | Standard Error 0.013 |
| TIO 18 µg OD | Change From Baseline Trough in 24-hour Weighted Mean FEV1 on Treatment Day 84 | 0.095 Liters | Standard Error 0.0138 |
p-value: 0.20195% CI: [-0.012, 0.055]ANCOVA
Secondary
Change From Baseline in Trough FEV1 at Treatment Day 84
Pulmonary function was measured by FEV1. Trough FEV1 was defined as the 24-hour FEV1 assessment, which was obtained on Day 84. Baseline is defined 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 84 values minus the Baseline value. Analysis was performed using an ANCOVA model with covariates of BL FEV1, exacerbation history and reversibility stratum, smoking status at screening, country, and treatment group.
Time frame: Baseline and Day 84
Population: ITT Population. Only participants with data available at the indicated time point were assessed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF/VI 100/25 µg OD | Change From Baseline in Trough FEV1 at Treatment Day 84 | 0.098 Liters | Standard Error 0.0133 |
| TIO 18 µg OD | Change From Baseline in Trough FEV1 at Treatment Day 84 | 0.093 Liters | Standard Error 0.014 |
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 of onset was calculated over 0 to 4 hours (5 minutes (min), 15 min, 30 min, 60 min, 120 min, and 240 min) post-dose. Time to onset was analyzed using a log-rank test, stratified by exacerbation history and reversibility stratum.
Time frame: Baseline and Day 1
Population: ITT Population. Only participants with data available at the indicated time point were assessed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FF/VI 100/25 µg OD | Time to Onset on Treatment Day 1 | 17.0 Minutes |
| TIO 18 µg OD | Time to Onset on Treatment Day 1 | 20.5 Minutes |