Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
FF/VI/UMEC, TRELEGY ELLIPTA, COPD, Effectiveness
Brief summary
The primary purpose of this study is to assess the effectiveness of TRELEGY ELLIPTA relative to non-ELLIPTA Multiple Inhaler Triple Therapies (MITT) for Chronic Obstructive Pulmonary Disease (COPD) control within the usual clinical practice setting. The study will be conducted once TRELEGY ELLIPTA has been approved in the countries in which the study will be conducted and is available commercially. This is a randomized, open-label, effectiveness, phase 4 study of 24 weeks' duration in COPD subjects to evaluate TRELEGY ELLIPTA (fluticasone furoate \[FF\]/vilanterol \[VI\]/umeclidinium bromide \[UMEC\]: 100 microgram \[mcg\]/62.5 mcg/25 mcg) inhalation powder taken once daily using a single ELLIPTA inhaler compared with any non-ELLIPTA MITT in the usual care setting. Effectiveness of TRELEGY ELLIPTA will be assessed by comparing proportion of COPD Assessment Test (CAT) responders at Week 24 between two treatment groups. TRELEGY and ELLIPTA are trademarks of GlaxoSmithKline (GSK) group of companies. The study will enroll approximately 3000 subjects.
Interventions
DRUGFF/UMEC/VI
FF is a dry white powder containing 100 mcg GW685698 blended with lactose in one blister in the first strip of the DPI. UMEC/VI is a dry white powder containing 62.5 mcg of UMEC and 25 mcg of VI per blister, both blended together with lactose and magnesium stearate in the second strip of the DPI.
Inhaled Corticosteroid (ICS) as prescribed by the physician.
DRUGLAMA
LAMA as prescribed by the physician.
DRUGLABA
LABA as prescribed by the physician.
DRUGCOPD rescue medications
Rescue medications for COPD will be prescribed and obtained according to usual practice.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Subjects will be randomized in a ratio of 1:1 to receive one of the following study treatment regimens: TRELEGY ELLIPTA once daily in the morning or Non-ELLIPTA MITT twice-daily treatment.
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Capable of giving signed informed consent. * Subjects with a documented physician diagnosis of COPD. * A score of \>=10 on the CAT at screening. * Subjects who have a history of treatment with systemic/oral corticosteroids, antibiotics and/or hospitalization for at least one COPD exacerbation in the 3 years prior to randomization. This will be captured through subject recall and/or medical records and must be documented in subject's notes. Prior use of systemic/oral corticosteroids and/or antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD. * Subjects currently receiving one of the non-ELLIPTA maintenance therapies listed below who have been prescribed it continually for at least 16 weeks prior to randomization. Continuous prescription is defined as a minimum of 60 days' prescription cover during the prior 16 weeks. The non-ELLIPTA maintenance therapy must be one of the following: Inhaled Corticosteroid (ICS) in combination with Long-acting Muscarinic Receptor Antagonist (LAMA) and Long Acting Beta-Agonist (LABA) (MITT) or LAMA and LABA used in combination as a dual therapy or LABA and ICS used in combination as a dual therapy. Subjects who are currently on a dual maintenance therapy for COPD must be considered by their physician to require a step-up to triple therapy. The reason for the physician decision to step- up must be documented. Subjects who are receiving only COPD medication on an 'as required' basis are not eligible. * Subjects must be aged \>=40 years of age at the time of signing the informed consent.
Exclusion criteria
* Women of child bearing potential: Women who are pregnant or lactating or are planning on becoming pregnant during the study. * Subjects with any life-threatening condition i.e. low probability, in the opinion of the investigator, of 6-month survival due to severity of COPD or comorbid condition. * Subjects with resolution of an exacerbation less than 2 weeks prior to visit 1, must not be randomized. Subjects may be rescreened 2 weeks after resolution of exacerbation (exacerbation is defined by treatment with systemic corticosteroids and/or antibiotic). * Subjects with historical or current evidence of uncontrolled or clinically significant disease. 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 effectiveness or safety analysis if the disease/condition exacerbated during the study. * A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, 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 investigator contraindicates study participation. * Subjects who, in the opinion of the treating investigator, are chronic users of oral corticosteroids for respiratory or other indications (if unsure discuss with the medical monitor prior to screening). Chronic use is defined as more than 14 days continuous use during the 12 weeks prior to visit 1. * Subjects taking any investigational drug treatment within 30 days prior to Visit 1 or within five half-lives (t½) of the prior investigational study (whichever is the longer of the two).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Responders and Non-responders Based on the Chronic Obstructive Pulmonary Disease Assessment Test (CAT) at Week 24 and Number of Participants With Imputed CAT Score at Week 24 | At Week 24 | The CAT is a 8-item questionnaire, used to measure the health status of par. with COPD. Par. rated their experience on a 6-point scale: 0 (no impact) to 5 (maximum impact). CAT score was calculated by summing the non-missing scores of the 8 items with a range of 0-40. Higher scores indicate greater disease impact. Responders were par. who had a change from Baseline score \>=2 at Week 24. Non-responders were the par. who had change from Baseline score \<2 at Week 24. Change from Baseline was calculated as Week 24 value minus the Baseline value (Day 1). A composite strategy was applied when intercurrent events of randomized treatment modification, change in pulmonary rehabilitation or start of oxygen therapy occurred, otherwise a treatment policy strategy was applied. Missing Week 24 CAT data were imputed assuming missing at random and are presented in a separate category. Number of responders, non-responders based on CAT and par. with imputed CAT score at Week 24 are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 24 | Baseline (Day 1) and at Week 24 | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 measurements were collected using a spirometer. Baseline was defined as the value recorded at Day 1. Change from Baseline was calculated as FEV1 value at Week 24 minus the Baseline value. A treatment policy strategy was used for the intercurrent events of randomized treatment discontinuation, randomized treatment modification, change of pulmonary rehabilitation status and start of oxygen therapy. Only those participants with non-missing covariates were included in the analysis. |
| Percentage of Participants Making at Least 1 Critical Error in Inhalation Technique at Week 24 | At Week 24 | Participants were trained on the correct use of their inhaler devices. All participants who had spirometry measured were to have an assessment of inhaler errors. During the assessment, participants were asked to demonstrate inhaler use when taking their regular dose of medication. A critical error is defined as an error that is most likely to result in no or significantly reduced medication being inhaled. These errors were recorded in an error checklist, during the assessment. A hypothetical strategy was used for the intercurrent event of randomized treatment modification. Percentage of participants making at least 1 critical error in inhalation technique at the Week 24 is presented. |
Countries
Germany, Netherlands, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
This was a Phase IV, open-label, randomized study to evaluate the effectiveness of TRELEGY ELLIPTA relative to non-ELLIPTA multiple inhaler triple therapies (MITT) for chronic obstructive pulmonary disease (COPD) control within the usual clinical practice setting. TRELEGY and ELLIPTA are registered trademarks of GlaxoSmithKline group of companies.
Pre-assignment details
A total of 3341 participants were screened and 3109 participants (Par.) were enrolled in this study. Of which, 3092 participants were randomized and received the study treatment. The remaining 17 participants were randomized in error (those who were recorded as screen failures and also randomized) and did not receive investigational product (IP).
Participants by arm
| Arm | Count |
|---|---|
| FF /UMEC/VI: 100 mcg/62.5 mcg/25 mcg by ELLIPTA DPI Eligible participants received a combination of fluticasone furoate (FF) blended with lactose in the first strip (100 microgram \[mcg\] per blister); and umeclidinium bromide (UMEC) and vilanterol (VI) blended with lactose and magnesium stearate in second strip (62.5 mcg UMEC per blister and 25 mcg VI per blister), a single inhalation once daily in the same TRELEGY ELLIPTA dry powder inhaler (DPI) via inhalation route for a period of 24 weeks. Participants were administered other prescribed COPD medications such as rescue medications according to usual practice, as suggested by physician. | 1,545 |
| Non-ELLIPTA MITT Eligible participants received the inhaled corticosteroid (ICS)/long-acting muscarinic receptor antagonist (LAMA)/long-acting beta agonist (LABA) products twice daily as prescribed by the physician for a period of 24 weeks. Participants were administered other prescribed COPD medications such as rescue medications according to usual practice, as suggested by physician. | 1,547 |
| Total | 3,092 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 9 |
| Overall Study | Lack of Efficacy | 3 | 1 |
| Overall Study | Lost to Follow-up | 18 | 25 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 15 | 17 |
Baseline characteristics
| Characteristic | FF /UMEC/VI: 100 mcg/62.5 mcg/25 mcg by ELLIPTA DPI | Non-ELLIPTA MITT | Total |
|---|---|---|---|
| Age, Continuous | 67.8 Years STANDARD_DEVIATION 8.78 | 67.8 Years STANDARD_DEVIATION 8.59 | 67.8 Years STANDARD_DEVIATION 8.68 |
| Race/Ethnicity, Customized Asian- Central/South Asian Heritage | 12 Participants | 7 Participants | 19 Participants |
| Race/Ethnicity, Customized Asian- East Asian Heritage | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian- South East Asian Heritage | 1 Participants | 6 Participants | 7 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 4 Participants | 7 Participants |
| Race/Ethnicity, Customized White and Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White- Arabic/North African Heritage | 6 Participants | 7 Participants | 13 Participants |
| Race/Ethnicity, Customized White- White/Caucasian/European Heritage | 1523 Participants | 1521 Participants | 3044 Participants |
| Sex: Female, Male Female | 708 Participants | 729 Participants | 1437 Participants |
| Sex: Female, Male Male | 837 Participants | 818 Participants | 1655 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 1,545 | 8 / 1,547 |
| other Total, other adverse events | 32 / 1,545 | 3 / 1,547 |
| serious Total, serious adverse events | 114 / 1,545 | 114 / 1,547 |
Outcome results
Primary
Number of Responders and Non-responders Based on the Chronic Obstructive Pulmonary Disease Assessment Test (CAT) at Week 24 and Number of Participants With Imputed CAT Score at Week 24
The CAT is a 8-item questionnaire, used to measure the health status of par. with COPD. Par. rated their experience on a 6-point scale: 0 (no impact) to 5 (maximum impact). CAT score was calculated by summing the non-missing scores of the 8 items with a range of 0-40. Higher scores indicate greater disease impact. Responders were par. who had a change from Baseline score \>=2 at Week 24. Non-responders were the par. who had change from Baseline score \<2 at Week 24. Change from Baseline was calculated as Week 24 value minus the Baseline value (Day 1). A composite strategy was applied when intercurrent events of randomized treatment modification, change in pulmonary rehabilitation or start of oxygen therapy occurred, otherwise a treatment policy strategy was applied. Missing Week 24 CAT data were imputed assuming missing at random and are presented in a separate category. Number of responders, non-responders based on CAT and par. with imputed CAT score at Week 24 are presented.
Time frame: At Week 24
Population: Intent-to-Treat (ITT) Population comprised of all randomized participants (any participant who received a randomization number), excluding those who were randomized in error (a screen failure and also randomized). Only those participants with non-missing covariates were included in the analysis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FF /UMEC/VI: 100 mcg/62.5 mcg/25 mcg by ELLIPTA DPI | Number of Responders and Non-responders Based on the Chronic Obstructive Pulmonary Disease Assessment Test (CAT) at Week 24 and Number of Participants With Imputed CAT Score at Week 24 | Responders | 731 Participants |
| FF /UMEC/VI: 100 mcg/62.5 mcg/25 mcg by ELLIPTA DPI | Number of Responders and Non-responders Based on the Chronic Obstructive Pulmonary Disease Assessment Test (CAT) at Week 24 and Number of Participants With Imputed CAT Score at Week 24 | Non-responders | 756 Participants |
| FF /UMEC/VI: 100 mcg/62.5 mcg/25 mcg by ELLIPTA DPI | Number of Responders and Non-responders Based on the Chronic Obstructive Pulmonary Disease Assessment Test (CAT) at Week 24 and Number of Participants With Imputed CAT Score at Week 24 | Participants with imputed CAT score | 52 Participants |
| Non-ELLIPTA MITT | Number of Responders and Non-responders Based on the Chronic Obstructive Pulmonary Disease Assessment Test (CAT) at Week 24 and Number of Participants With Imputed CAT Score at Week 24 | Responders | 616 Participants |
| Non-ELLIPTA MITT | Number of Responders and Non-responders Based on the Chronic Obstructive Pulmonary Disease Assessment Test (CAT) at Week 24 and Number of Participants With Imputed CAT Score at Week 24 | Non-responders | 835 Participants |
| Non-ELLIPTA MITT | Number of Responders and Non-responders Based on the Chronic Obstructive Pulmonary Disease Assessment Test (CAT) at Week 24 and Number of Participants With Imputed CAT Score at Week 24 | Participants with imputed CAT score | 92 Participants |
p-value: <0.00195% CI: [1.13, 1.51]Regression, Logistic
Secondary
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 24
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 measurements were collected using a spirometer. Baseline was defined as the value recorded at Day 1. Change from Baseline was calculated as FEV1 value at Week 24 minus the Baseline value. A treatment policy strategy was used for the intercurrent events of randomized treatment discontinuation, randomized treatment modification, change of pulmonary rehabilitation status and start of oxygen therapy. Only those participants with non-missing covariates were included in the analysis.
Time frame: Baseline (Day 1) and at Week 24
Population: FEV1 Population comprised of all participants of the ITT population for whom a spirometry assessment was performed at any of Visit 1 (Day 1) or Visit 2 (Week 24). Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF /UMEC/VI: 100 mcg/62.5 mcg/25 mcg by ELLIPTA DPI | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 24 | 1.446 Liters | Standard Error 0.0105 |
| Non-ELLIPTA MITT | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 24 | 1.396 Liters | Standard Error 0.0108 |
p-value: <0.00195% CI: [0.026, 0.073]ANCOVA
Secondary
Percentage of Participants Making at Least 1 Critical Error in Inhalation Technique at Week 24
Participants were trained on the correct use of their inhaler devices. All participants who had spirometry measured were to have an assessment of inhaler errors. During the assessment, participants were asked to demonstrate inhaler use when taking their regular dose of medication. A critical error is defined as an error that is most likely to result in no or significantly reduced medication being inhaled. These errors were recorded in an error checklist, during the assessment. A hypothetical strategy was used for the intercurrent event of randomized treatment modification. Percentage of participants making at least 1 critical error in inhalation technique at the Week 24 is presented.
Time frame: At Week 24
Population: Critical error Population comprised of all participants of the ITT population for whom a critical error assessment was performed at Visit 2 (Week 24). Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FF /UMEC/VI: 100 mcg/62.5 mcg/25 mcg by ELLIPTA DPI | Percentage of Participants Making at Least 1 Critical Error in Inhalation Technique at Week 24 | 6 Percentage of Participants |
| Non-ELLIPTA MITT | Percentage of Participants Making at Least 1 Critical Error in Inhalation Technique at Week 24 | 3 Percentage of Participants |
p-value: 0.10395% CI: [0.87, 4.53]Regression, Logistic