Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
COPD, Bronchitis, Chronic, Emphysema
Brief summary
The objective is to provide data supporting the use of LAS40464 as an efficacious and safe maintenance bronchodilator treatment of patients with Chronic Obstructive Pulmonary Disease (COPD).
Detailed description
This Phase III study seeks to confirm the long-term bronchodilator efficacy and effects on COPD related health status and other secondary parameters as well as the safety of two doses of the combination of aclidinium bromide/formoterol FDC (FDC 400/12 μg and 400/6 μg) compared with aclidinium bromide monotherapy 400 μg, formoterol monotherapy 12 μg and placebo.
Interventions
Inhaled Aclidinium/formoterol Fixed Dose Combination (FDC) low dose (400/6 μg), twice per day
Inhaled Aclidinium 400 μg, twice per day
DRUGPlacebo
Inhaled dose-matched placebo, twice per day
DRUGFormoterol Fumarate
Inhaled Formoterol 12 μg, twice per day
Sponsors
AstraZeneca
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
* Adult male or non-pregnant, non-lactating female aged ≥40. Women of childbearing potential are allowed to enter the trial if they show to have a negative serum pregnancy test at the Screening Visit and are using, during the last two months before the Screening Visit, at least one medically approved and highly effective method of birth control defined as those which result in a low failure rate (i.e less than 1% per year) when used consistently and correctly such as implants, injectables, oral contraceptives combined with at least one barrier method, hormonal Intrauterine Devices (IUDs), sexual abstinence or vasectomy of the partner. * Current or ex-cigarette smoker, with a smoking history of at least 10 pack-years. * Patient with a clinical diagnosis of stable COPD according to the Global Initiative for Chronic Lung Disease GOLD Guidelines at the Screening Visit. * Patient whose FEV1/FVC (Forced Vital Capacity) at the Screening Visit measured between 10-15 minutes post inhalation of 400 micrograms of salbutamol is \< 70% (i.e., 100 x Post-salbutamol FEV1 /FVC \< 70%). * Patient with a diagnosis of moderate to severe COPD according to the GOLD Guidelines classification (stages II and III) at the Screening Visit: FEV1 measured between 10-15 minutes post inhalation of 400 micro grams of salbutamol is 30% \< FEV1 \< 80% of the predicted normal value (i.e., 100 x Post-salbutamol FEV1/ Predicted FEV1 must be \< 80% and ≥ 30%). * Patient must be able to perform repeatable pulmonary function testing for FEV1 according to American Thoracic Society/European Respiratory Society ATS/ERS 2005 criteria at Screening Visit. * Patient who is 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. * Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the 6 weeks before Screening Visit. * Patient hospitalised for COPD exacerbation within 3 months prior to Screening Visit. * Clinically significant respiratory conditions defined as: * Known active tuberculosis. * History of interstitial lung or massive pulmonary thromboembolic disease. * Pulmonary resection or lung volume reduction surgery within 12 months prior to Screening Visit. * History of lung transplantation. * History of bronchiectasis secondary to respiratory diseases others than COPD (e.g., cystic fibrosis, Kartagener's syndrome, etc). * Known a1-antitrypsin deficiency. * Patients who in the Investigator's opinion might have needed to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to screening. * Use of long-term oxygen therapy (≥ 15 hours/day). * Patients who did not maintain regular day/night, waking/sleeping cycles including night shift workers (eg, history of sleep apnoea syndrome, any condition related to sleep disturbances such as restless-legs syndrome or somnambulism). * Clinically significant cardiovascular conditions defined as: * Myocardial infarction within the 6 months prior to screening. * Thoracic surgery within 12 months prior to screening. * Unstable angina or unstable arrhythmia which had required changes in the pharmacological therapy or other intervention within 12 months prior to screening, or newly diagnosed arrhythmia within the previous 3 months prior to screening. * Hospitalisation within 12 months prior to screening for heart failure functional classes III (marked limitation of activity and only comfortable at rest) and IV (need of complete rest, confinement to bed or chair, discomfort at any physical activity and presence of symptoms at rest) as per the New York Heart Association. * Patients (with or without pharmacological therapy) with resting systolic blood pressure (SBP) ≥200 mmHg, a resting diastolic blood pressure (DBP) ≥120 mmHg, or a resting heart rate ≥105 beats per minute (bpm) at screening and at Visit 1 prior to randomisation. * Patients with interval corrected for heart rate QTc \[calculated according to formulae (QTc=QT/RR1/2) \> 470 msec as indicated in the centralised reading report assessed at Screening Visit. * Patients with clinically relevant abnormalities in the clinical laboratory tests, ECG parameters (other than QT interval corrected using Bazett's formula \[QTcB\]) or in the physical examination at screening, if the abnormality defined a disease state listed as
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1) | Baseline and Week 24 |
| Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | Baseline and Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Transition Dyspnoea Index (TDI) Focal Score | Baseline and Week 24 | Evaluation of dyspnea was performed by an independent interviewer experienced in taking a respiratory history The TDI includes three categories: functional impairment which determines the impact of breathlessness on the ability to perform activities, magnitude of task which determines the type of task that caused breathlessness and magnitude of effort which establishes the level of effort needed to evoke breathlessness Each category ranges from minus three (-3; major deterioration) to plus three (+3; major improvement) including a zero (0) score to indicate 'no change' The three categories are totalled to obtain a focal score (total score) ranging from minus nine (-9), including zero (0), to plus nine (+9) Provision is made for circumstances when dyspnoea could not be rated - if reduction of activities, effort or functional impairment was caused by reasons other than respiratory A change of 1 unit in TDI is used as the criterion for a minimal meaningful improvement |
| Change From Baseline in St. George´s Respiratory Questionnaire (SGRQ) Total Score | Baseline and Week 24 | SGRQ is a standardised, self-administered tool for measuring impaired health and perceived well-being in respiratory diseases; a validated electronic version of the questionnaire in the relevant validated languages was used in this study The questionnaire contains 50 items divided into three dimensions (Symptoms, Activity and Impact) Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100: zero (0) score indicating no impairment of quality of life The total SGRQ score ranging from 0 to 100 is a summary score utilising responses to all items calculated using weights attached to each item of the questionnaire Higher scores indicate poorer health and change of 4 units in the SGRQ has been determined to be the threshold for a clinically relevant change in health status |
Countries
Austria, Belgium, Bulgaria, Croatia, Czechia, Denmark, Finland, France, Germany, Hungary, Italy, Netherlands, Poland, Romania, Russia, Slovakia, South Africa, South Korea, Spain, Sweden, Ukraine, United Kingdom
Participant flow
Recruitment details
The study was conducted in 22 countries (Austria, Belgium, Bulgaria, Croatia, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, the Netherlands, Poland, Romania, Russia, Slovakia, South Africa, South Korea, Spain, Sweden, Ukraine and UK). The first patient was screened in October 2011 and the last patient visit was in January 2013
Pre-assignment details
In total, 2443 patients were screened, of whom 1729 were considered eligible and were randomized into the study. 714/2443 patients were not randomized due to screening failure (primarily for non-fulfillment of inclusion/exclusion criteria)
Participants by arm
| Arm | Count |
|---|---|
| Placebo Administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®) | 194 |
| Aclidinium/Formoterol 400/12 μg Administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®) | 385 |
| Aclidinium/Formoterol 400/6 μg Administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®) | 381 |
| Aclidinium 400 μg Administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®) | 385 |
| Formoterol 12 μg Administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®) | 384 |
| Total | 1,729 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 12 | 10 | 11 | 11 |
| Overall Study | Lack of Efficacy | 6 | 0 | 4 | 5 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 1 | 1 |
| Overall Study | Other, including COPD exacerbation | 3 | 5 | 2 | 8 | 5 |
| Overall Study | Protocol Violation | 4 | 6 | 9 | 9 | 6 |
| Overall Study | Withdrawal by Subject | 14 | 10 | 14 | 16 | 19 |
Baseline characteristics
| Characteristic | Placebo | Aclidinium/Formoterol 400/12 μg | Aclidinium/Formoterol 400/6 μg | Aclidinium 400 μg | Formoterol 12 μg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 64.2 Years STANDARD_DEVIATION 8 | 62.7 Years STANDARD_DEVIATION 8.1 | 62.9 Years STANDARD_DEVIATION 7.7 | 63.1 Years STANDARD_DEVIATION 8.2 | 63.4 Years STANDARD_DEVIATION 7.8 | 63.2 Years STANDARD_DEVIATION 8 |
| Gender Female | 56 Participants | 124 Participants | 122 Participants | 129 Participants | 129 Participants | 560 Participants |
| Gender Male | 138 Participants | 261 Participants | 259 Participants | 256 Participants | 255 Participants | 1169 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 42 / 194 | 82 / 385 | 84 / 381 | 94 / 385 | 105 / 384 |
| serious Total, serious adverse events | 12 / 194 | 23 / 385 | 18 / 381 | 16 / 385 | 14 / 384 |
Outcome results
Primary
Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1)
Time frame: Baseline and Week 24
Population: ITT Population defined as all randomized patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1) | -0.030 Liters | Standard Error 0.018 |
| Aclidinium/Formoterol 400/12 μg | Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1) | 0.269 Liters | Standard Error 0.013 |
| Aclidinium/Formoterol 400/6 μg | Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1) | 0.213 Liters | Standard Error 0.013 |
| Aclidinium 400 μg | Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1) | 0.144 Liters | Standard Error 0.013 |
| Formoterol 12 μg | Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1) | 0.129 Liters | Standard Error 0.013 |
p-value: <0.000195% CI: [0.09, 0.16]Mixed Models Analysis
p-value: 0.000195% CI: [0.034, 0.105]Mixed Models Analysis
Primary
Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1)
Time frame: Baseline and Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | -0.061 Liters | Standard Error 0.018 |
| Aclidinium/Formoterol 400/12 μg | Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | 0.083 Liters | Standard Error 0.012 |
| Aclidinium/Formoterol 400/6 μg | Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | 0.050 Liters | Standard Error 0.012 |
| Aclidinium 400 μg | Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | 0.056 Liters | Standard Error 0.012 |
| Formoterol 12 μg | Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | -0.002 Liters | Standard Error 0.012 |
p-value: <0.000195% CI: [0.051, 0.119]Mixed Models Analysis
p-value: 0.002295% CI: [0.019, 0.087]Mixed Models Analysis
Secondary
Change From Baseline in St. George´s Respiratory Questionnaire (SGRQ) Total Score
SGRQ is a standardised, self-administered tool for measuring impaired health and perceived well-being in respiratory diseases; a validated electronic version of the questionnaire in the relevant validated languages was used in this study The questionnaire contains 50 items divided into three dimensions (Symptoms, Activity and Impact) Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100: zero (0) score indicating no impairment of quality of life The total SGRQ score ranging from 0 to 100 is a summary score utilising responses to all items calculated using weights attached to each item of the questionnaire Higher scores indicate poorer health and change of 4 units in the SGRQ has been determined to be the threshold for a clinically relevant change in health status
Time frame: Baseline and Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in St. George´s Respiratory Questionnaire (SGRQ) Total Score | -6.511 Score on a scale | Standard Error 1.029 |
| Aclidinium/Formoterol 400/12 μg | Change From Baseline in St. George´s Respiratory Questionnaire (SGRQ) Total Score | -7.164 Score on a scale | Standard Error 0.703 |
| Aclidinium/Formoterol 400/6 μg | Change From Baseline in St. George´s Respiratory Questionnaire (SGRQ) Total Score | -8.339 Score on a scale | Standard Error 0.706 |
| Aclidinium 400 μg | Change From Baseline in St. George´s Respiratory Questionnaire (SGRQ) Total Score | -5.801 Score on a scale | Standard Error 0.71 |
| Formoterol 12 μg | Change From Baseline in St. George´s Respiratory Questionnaire (SGRQ) Total Score | -5.579 Score on a scale | Standard Error 0.706 |
p-value: 0.59895% CI: [-3.082, 1.776]Mixed Models Analysis
p-value: 0.140695% CI: [-4.259, 0.604]Mixed Models Analysis
Secondary
Change in Transition Dyspnoea Index (TDI) Focal Score
Evaluation of dyspnea was performed by an independent interviewer experienced in taking a respiratory history The TDI includes three categories: functional impairment which determines the impact of breathlessness on the ability to perform activities, magnitude of task which determines the type of task that caused breathlessness and magnitude of effort which establishes the level of effort needed to evoke breathlessness Each category ranges from minus three (-3; major deterioration) to plus three (+3; major improvement) including a zero (0) score to indicate 'no change' The three categories are totalled to obtain a focal score (total score) ranging from minus nine (-9), including zero (0), to plus nine (+9) Provision is made for circumstances when dyspnoea could not be rated - if reduction of activities, effort or functional impairment was caused by reasons other than respiratory A change of 1 unit in TDI is used as the criterion for a minimal meaningful improvement
Time frame: Baseline and Week 24
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Transition Dyspnoea Index (TDI) Focal Score | 1.215 Score on a scale | Standard Error 0.241 |
| Aclidinium/Formoterol 400/12 μg | Change in Transition Dyspnoea Index (TDI) Focal Score | 2.508 Score on a scale | Standard Error 0.162 |
| Aclidinium/Formoterol 400/6 μg | Change in Transition Dyspnoea Index (TDI) Focal Score | 2.377 Score on a scale | Standard Error 0.165 |
| Aclidinium 400 μg | Change in Transition Dyspnoea Index (TDI) Focal Score | 2.112 Score on a scale | Standard Error 0.165 |
| Formoterol 12 μg | Change in Transition Dyspnoea Index (TDI) Focal Score | 2.062 Score on a scale | Standard Error 0.164 |
p-value: <0.000195% CI: [0.728, 1.859]Mixed Models Analysis
Comparison: Adjusted by BDI baseline score and age as covariates, with treatment group, gender, smoking-status, visit, and group-by-visit as fixed effect factorsp-value: <0.000195% CI: [0.593, 1.73]Mixed Models Analysis