Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Brief summary
The purpose of the study is to compare the efficacy, safety and tolerability of aclidinium bromide/formoterol fumarate and salmeterol/fluticasone propionate in patients with chronic obstructive pulmonary disease (COPD)
Interventions
DRUGAclidinium Bromide / Formoterol Fumarate
DRUGSalmeterol / Fluticasone
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult male or non-pregnant, non-lactating female aged ≥40. * Current or ex-cigarette smoker, with a smoking history of at least 10 pack-years * Patients with a clinical diagnosis of COPD according to GOLD guidelines 2013, with a post-bronchodilator FEV1 \<80%, and FEV1/FVC \< 70% at Screening Visits * Symptomatic patients with a COPD assessment test (CAT) ≥10 at Screening and Randomisation Visits * Patient must be able to perform repeatable pulmonary function testing for FEV1 according to ATS/ERS 2005 criteria at Screening Visits * Patients eligible and able to participate in the trial and who consent to do so in writing after the purpose and nature of the investigation have been explained
Exclusion criteria
* History or current diagnosis of asthma * Development of a respiratory tract infection or COPD exacerbation within 6 weeks (or 3 months if hospitalisation was required) before the Screening Visit or during the run-in period * Clinically significant respiratory conditions * Type I or uncontrolled Type II diabetes, uncontrolled hypo- or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled or untreated hypertension * Patients who, in the investigator's opinion, may need to start a pulmonary rehabilitation programme during the study and/or patients who started/finished it within 3 months prior to Screening Visit * Use of long-term oxygen therapy (≥15 hours/day) * Patients treated on daily basis with triple therapy (LABA+LAMA+ICS) within 4 weeks prior to the Screening Visit * Patient who does not maintain regular day/night, waking/sleeping cycles including night shift workers * Clinically significant cardiovascular conditions * Patient with clinically relevant abnormalities in the results of the clinical laboratory tests, ECG parameters or in the physical examination at the Screening Visit * Patient with a history of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm) * Patient with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention, or patients with symptomatic non-stable prostatic hypertrophy * Patient with known non-controlled history of infection with human immunodeficiency virus (HIV) and/or active hepatitis * History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer * Patient with any other serious or uncontrolled physical or mental dysfunction * Patient with a history (within 2 years prior to Screening Visit) of drug and/or alcohol abuse that may prevent study compliance based on investigator judgment * Patient unlikely to be cooperative or that can't comply with the study procedures * Patient treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to Screening Visit * Patient who intend to use any concomitant medication not permitted by this protocol or who have not undergone the required stabilization periods for prohibited medication * Any other conditions that, in the investigator's opinion, might indicate the patient to be unsuitable for the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Forced Expiratory Volume in One Second (FEV1) at Week 24 | At Week 24 | Peak FEV1 define at the highest value observed in the 3h after the morning IMP administration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Transition Dyspnoea Index (TDI) Focal Score at Week 24 | At Week 24 | The TDI includes the same 3 categories as BDI and 7 ratings indicating the magnitude of the change from baseline in each category: from -3 (major deterioration) to zero (no change) to +3 (major improvement). Category scores are added to compute the Focal Score (from -9 to 9) |
Countries
Austria, Bulgaria, Canada, Czechia, France, Germany, Hungary, Italy, Lithuania, Netherlands, Poland, South Africa, Spain, United Kingdom
Participant flow
Recruitment details
This study was conducted at 140 activated sites. A total of 121 sites randomised patients. The first patient was screened in Oct 2013 and the last patient visit was in Aug 2014.
Pre-assignment details
Patients fulfilling inclusion/exclusion criteria at the time of the screening visit were entered into a run-in period of 14-21 days to assess disease stability.
Participants by arm
| Arm | Count |
|---|---|
| Aclidinium Bromide / Formoterol Fumarate Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks | 467 |
| Salmeterol / Fluticasone Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks | 466 |
| Total | 933 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 22 | 23 |
| Overall Study | Lack of Efficacy | 7 | 5 |
| Overall Study | Lost to Follow-up | 1 | 6 |
| Overall Study | Other or Progressive Disease | 5 | 12 |
| Overall Study | Protocol Violation | 8 | 9 |
| Overall Study | Withdrawal by Subject | 23 | 24 |
Baseline characteristics
| Characteristic | Salmeterol / Fluticasone | Total | Aclidinium Bromide / Formoterol Fumarate |
|---|---|---|---|
| Age, Customized Age (years), mean (SD) | 63.3 years STANDARD_DEVIATION 7.5 | 63.4 years STANDARD_DEVIATION 7.8 | 63.5 years STANDARD_DEVIATION 8.1 |
| Region of Enrollment Austria | 24 participants | 47 participants | 23 participants |
| Region of Enrollment Bulgaria | 32 participants | 62 participants | 30 participants |
| Region of Enrollment Canada | 6 participants | 18 participants | 12 participants |
| Region of Enrollment Czech Republic | 14 participants | 25 participants | 11 participants |
| Region of Enrollment France | 4 participants | 14 participants | 10 participants |
| Region of Enrollment Germany | 136 participants | 254 participants | 118 participants |
| Region of Enrollment Hungary | 48 participants | 98 participants | 50 participants |
| Region of Enrollment Italy | 5 participants | 11 participants | 6 participants |
| Region of Enrollment Lithuania | 10 participants | 27 participants | 17 participants |
| Region of Enrollment Netherlands | 11 participants | 22 participants | 11 participants |
| Region of Enrollment Poland | 55 participants | 122 participants | 67 participants |
| Region of Enrollment South Africa | 66 participants | 134 participants | 68 participants |
| Region of Enrollment Spain | 34 participants | 62 participants | 28 participants |
| Region of Enrollment United Kingdom | 21 participants | 37 participants | 16 participants |
| Sex: Female, Male Female | 166 Participants | 326 Participants | 160 Participants |
| Sex: Female, Male Male | 300 Participants | 607 Participants | 307 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 124 / 467 | 135 / 466 |
| serious Total, serious adverse events | 35 / 467 | 33 / 466 |
Outcome results
Primary
Peak Forced Expiratory Volume in One Second (FEV1) at Week 24
Peak FEV1 define at the highest value observed in the 3h after the morning IMP administration
Time frame: At Week 24
Population: ITT population: randomized patients who took at least one dose of IMP and have a baseline FEV1 assessment.~PP population: subset of ITT constituted by patients who met all inclusion/exclusion criteria liable to affect the efficacy ssessment, attained sufficient compliance to treatment and did not present serious deviations of the protocol.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium Bromide / Formoterol Fumarate | Peak Forced Expiratory Volume in One Second (FEV1) at Week 24 | 1.655 Liters | Standard Error 0.011 |
| Salmeterol / Fluticasone | Peak Forced Expiratory Volume in One Second (FEV1) at Week 24 | 1.562 Liters | Standard Error 0.011 |
Comparison: This sample size of 900 had 90% power to show that the lower bound of the two-sided 95% confidence interval for the difference between Aclidinium bromide 400 μg/Formoterol Fumarate 12 μg and SeretideTM AccuhalerTM (50/500 μg) in Peak FEV1 at 24 weeks is above -0,055 Lp-value: <0.00195% CI: [0.063, 0.123]MMRM
Secondary
Transition Dyspnoea Index (TDI) Focal Score at Week 24
The TDI includes the same 3 categories as BDI and 7 ratings indicating the magnitude of the change from baseline in each category: from -3 (major deterioration) to zero (no change) to +3 (major improvement). Category scores are added to compute the Focal Score (from -9 to 9)
Time frame: At Week 24
Population: PP population defined as a subset of ITT constituted by patients who met all inclusion/exclusion criteria liable to affect the efficacy ssessment, attained sufficient compliance to treatment and did not present serious deviations of the protocol.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium Bromide / Formoterol Fumarate | Transition Dyspnoea Index (TDI) Focal Score at Week 24 | 1.9 TDI Focal Score | Standard Error 0.17 |
| Salmeterol / Fluticasone | Transition Dyspnoea Index (TDI) Focal Score at Week 24 | 1.9 TDI Focal Score | Standard Error 0.17 |
Comparison: The total sample size provided 81% nominal power to show that the lower bound of the two-sided 95 confidence interval for the difference between Aclidinium bromide 400 μg/Formoterol fumarate 12 μg and SeretideTM AccuhalerTM (50/500 μg) in transitional dyspnoea index (TDI) at 24 weeks is above -0,5p-value: >0.0595% CI: [-0.46, 0.46]MMRM