Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
umeclidinium bromide (UMEC), vilanterol (VI), salmeterol (SAL), fluticasone propionate (FP), Novel Dry Powder Inhaler (NDPI), Chronic obstructive pulmonary disease, GW642444, GSK573719, lung function
Brief summary
This is a multicenter, randomized, double-blind, double-dummy, parallel group study. The purpose of this study is to compare the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) and fluticasone propionate/salmeterol (FSC) in subjects with COPD. Subjects who meet the eligibility criteria at Screening will complete a 7 to 14 day Run-in period. At the end of the run-in period, approximately 710 eligible subjects will be equally randomized (to complete at least 568 evaluable subjects) to one of the 2 treatment groups for 12 weeks: 1. UMEC/VI 62.5/25 micrograms (mcg) administered as one inhalation once-daily in the morning via the Novel dry powder inhaler (NDPI) + placebo administered as one inhalation each morning and evening via single multidose powdered inhaler (ACCUHALER/DISKUS) or 2. FSC 250/50 mcg administered as one inhalation each morning and evening via ACCUHALER/DISKUS + placebo administered once-daily in the morning via NDPI. A safety Follow-up assessment will be conducted approximately 7 days after the end of the study treatment (Early Withdrawal, if applicable). The total duration of subject participation will be approximately 15 weeks.
Interventions
Dry white powder delivered via NDPI (2 strips with 30 blisters each, first containing UMEC 62.5 mcg per blister and second containing VI 25 mcg per blister), administered as one inhalation of UMEC/VI 62.5/25 mcg once-daily in the morning
Dry white powder delivered via ACCUHALER/DISKUS (1 strip with 60 blisters, containing 250 mcg fluticasone propionate and 50 mcg salmeterol per blister), administered as one inhalation of FSC 250/50 mcg each morning and evening
DRUGPlacebo
Placebo will be administered via ACCUHALER/DISKUS or NDPI. Dry white powder administered as one inhalation each morning and evening via ACCUHALER/DISKUS (1 strip with 60 blisters containing placebo) OR once-daily in the morning via NDPI (2 strips with 30 blisters each, containing 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
* Type of subject: Outpatient * A signed and dated written informed consent prior to study participation * Male or female subjects, 40 years of age or older at Visit 1 * A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). - A female is eligible to enter and participate in the study if she is of: Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods as listed in the protocol used consistently and correctly. * An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society as follows: Chronic obstructive pulmonary disease is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences * Smoking history: Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years (number of pack years = \[number of cigarettes per day/20\] x number of years smoked \[e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years\]). Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Pipe and/or cigar use cannot be used to calculate pack year history * Severity of disease: A pre and post-salbutamol FEV1/Forced Vital Capacity (FVC) ratio of \<0.70 and a post-salbutamol FEV1 of \>=30% and \<=70% of predicted normal values calculated using National Health and Nutrition Examination Survey (NHANES) III reference equations at Visit 1 * Dyspnea: A score of \>=2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1
Exclusion criteria
* Women who are pregnant or lactating or are planning on becoming pregnant during the study * A current diagnosis of asthma * Other Respiratory Disorders: Known α-1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer are absolute exclusionary conditions. A subject, who, in the opinion of the investigator, has any other significant respiratory condition in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease. Inactive tuberculosis in more than one lobe is exclusionary. 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 hematological 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 * Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, corticosteroid, 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 for pneumonia within 12 weeks prior to Visit 1 * History of COPD Exacerbation: A documented history of at least one COPD exacerbation in the 12 months prior to Visit 1 that required either oral corticosteroids, antibiotics, and/or hospitalization. Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, sputum volume, or sputum purulence * Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1) * 12-Lead Electrocardiogram (ECG): An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1. Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. * Medication Prior to Spirometry: Unable to withhold salbutamol for the 4 hour period required prior to spirometry testing at each study visit * Medications Prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1: Depot corticosteroids - 12 weeks, Systemic, oral or parenteral corticosteroids - 6 weeks, Antibiotics (for lower respiratory tract infection) - 6 weeks, Cytochrome P450 3A4 strong inhibitors - 6 weeks, Herbal medications potentially containing oral or systemic steroids - 6 weeks, Inhaled corticosteroids (ICS) - 30 days, Long-acting beta2-agonist (LABA)/ICS combination products - 30 days, Phosphodiesterase 4 (PDE4) inhibitors (e.g., roflumilast) - 14 days, Inhaled long-acting anticholinergics - 7 days, Theophyllines - 48 hours, Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton) - 48 hours, Oral beta2-agonists Long-acting-48 hours/Short-acting - 12 hours, Inhaled long acting beta2-agonists (LABA, e.g., salmeterol, formoterol, indacaterol) - 48 hours, Inhaled sodium cromoglycate or nedocromil sodium - 24 hours, Inhaled short acting beta2-agonists - 4 hours, Inhaled short-acting anticholinergics - 4 hours, Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products - 4 hours, Any other investigational medication - 30 days or within 5 drug half-lives (whichever is longer) * 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., 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: A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator * Inability to read: A subject will not be eligible for the study if in the opinion of the investigator the subject cannot read
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-hour Weighted-mean Serial FEV1 on Treatment Day 84 | Baseline and Day 84 | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Weighted mean is calculated from the pre-dose FEV1 and post-dose FEV1 measurements at 5 and 15 minutes and 1, 3, 6, 9, 12 (pre-evening dose), 13, 15, 18, 23, and 24 hours after the morning dose. Change from Baseline was calculated as the value at Day 84 minus the value at Baseline. Analysis was performed using an analysis of covariance of treatment, Baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), and smoking status. par.=participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough FEV1 on Day 85 | Baseline and Day 85 | Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after morning dosing/11 and 12 hours after evening dosing on Day 84. Change from Baseline is calculated as the Day 85 value minus the Baseline value. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, day, and day by Baseline and day by treatment interactions. |
Countries
Argentina, Chile, Greece, Peru, Romania, Ukraine, United States
Participant flow
Pre-assignment details
A total of 707 participants, representing the enrolled participants, were randomized to study treatment. Of these, 706 comprised the Intent-to-Treat Population (participants randomized to treatment who received \>=1 dose of randomized study medication in the treatment period).
Participants by arm
| Arm | Count |
|---|---|
| UMEC/VI 62.5/25 µg QD Participants were randomized to umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 micrograms (µg) once-daily (QD) treatment in the morning via a dry powder inhaler (DPI) and placebo in the morning and evening via a separate DPI. | 353 |
| FSC 250/50 µg BID Participants were randomized to fluticasone propionate/salmeterol (FSC) 250/50 µg twice-daily (BID) treatment in the morning and evening via a DPI and placebo in the morning via a separate DPI. | 353 |
| Total | 706 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 10 |
| Overall Study | Lack of Efficacy | 9 | 7 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Protocol Violation | 7 | 5 |
| Overall Study | Withdrawal by Subject | 10 | 12 |
Baseline characteristics
| Characteristic | FSC 250/50 µg BID | Total | UMEC/VI 62.5/25 µg QD |
|---|---|---|---|
| Age, Continuous | 63.0 Years STANDARD_DEVIATION 8.91 | 62.8 Years STANDARD_DEVIATION 8.97 | 62.5 Years STANDARD_DEVIATION 9.05 |
| Race/Ethnicity, Customized African American/African Heritage | 3 Participants | 7 Participants | 4 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 5 Participants | 10 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European | 342 Participants | 683 Participants | 341 Participants |
| Sex: Female, Male Female | 109 Participants | 209 Participants | 100 Participants |
| Sex: Female, Male Male | 244 Participants | 497 Participants | 253 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 353 | 25 / 353 |
| serious Total, serious adverse events | 6 / 353 | 10 / 353 |
Outcome results
Primary
Change From Baseline in 24-hour Weighted-mean Serial FEV1 on Treatment Day 84
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Weighted mean is calculated from the pre-dose FEV1 and post-dose FEV1 measurements at 5 and 15 minutes and 1, 3, 6, 9, 12 (pre-evening dose), 13, 15, 18, 23, and 24 hours after the morning dose. Change from Baseline was calculated as the value at Day 84 minus the value at Baseline. Analysis was performed using an analysis of covariance of treatment, Baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), and smoking status. par.=participants.
Time frame: Baseline and Day 84
Population: Intent-to-Treat (ITT) Population: all par. randomized to treatment who received \>=1 dose of randomized study medication in the treatment period. Only par. with analyzable data at the indicated time point were assessed, but all par. without missing covariate information and with \>=1 post-Baseline measurement were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| UMEC/VI 62.5/25 µg QD | Change From Baseline in 24-hour Weighted-mean Serial FEV1 on Treatment Day 84 | 0.165 Liters | Standard Error 0.013 |
| FSC 250/50 µg BID | Change From Baseline in 24-hour Weighted-mean Serial FEV1 on Treatment Day 84 | 0.091 Liters | Standard Error 0.0131 |
p-value: <0.00195% CI: [0.038, 0.11]ANCOVA
Secondary
Change From Baseline in Trough FEV1 on Day 85
Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after morning dosing/11 and 12 hours after evening dosing on Day 84. Change from Baseline is calculated as the Day 85 value minus the Baseline value. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, day, and day by Baseline and day by treatment interactions.
Time frame: Baseline and Day 85
Population: ITT Population. Only those participants with analyzable data at the indicated time point were assessed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| UMEC/VI 62.5/25 µg QD | Change From Baseline in Trough FEV1 on Day 85 | 0.154 Liters | Standard Error 0.0133 |
| FSC 250/50 µg BID | Change From Baseline in Trough FEV1 on Day 85 | 0.072 Liters | Standard Error 0.0134 |