Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
COPD
Brief summary
The present study is planned to evaluate the effect of the aclidinium bromide/formoterol fumarate 400/12 μg FDC BID on the hyperinflation, exercise endurance and physical activity in patients with moderate to severe COPD. Additionally, the effect of the behavioural intervention on top of aclidinium bromide/formoterol fumarate 400/12 μg will be assessed both on the exercise endurance and the physical activity.
Interventions
DRUGAclidinium/Formoterol
Aclidinium bromide/Formoterol fumarate FDC 400/12μg dry powder for oral inhalation twice daily via Genuair inhaler
DRUGPlacebo
Dose-matched placebo dry powder for oral inhalation twice daily via Genuair inhaler
Sponsors
Menarini Group
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Males and non-pregnant, non-lactating females aged ≥ 40. 2. Patients with a clinical diagnosis of COPD according to GOLD guidelines 2014, with a post bronchodilator FEV1 ≥ 40% and \< 80% of the predicted value and FEV1/FVC \< 70% at Visit 1. 3. Functional residual capacity (FRC) measured by body plethysmography at Visit 1 ≥ 120% of predicted value. 4. Patients with modified Medical Research Council dyspnea scale (mMRC) ≥ 2 at Visit 1. 5. Current or former cigarette smokers with a smoking history of at least 10 pack-years at Visit 1 6. Patients willing to participate in the telecoaching program during the four last weeks and to enhance their physical activity 7. Patients who understand and are able to follow the study procedures, are cooperative and are willing to participate in the study as indicated by signing the informed consent.
Exclusion criteria
1. History or current diagnosis of asthma. 2. Any respiratory tract infection (including upper respiratory tract) or COPD exacerbation in the 6 weeks prior to Visit 1 or during the run-in period. 3. Patients who have been hospitalised for an acute COPD exacerbation within 3 months prior to Visit 1 or during the run-in period. 4. Clinically significant respiratory conditions other than COPD. 5. Use of long-term oxygen therapy (≥ 15 hours/day). 6. Oxygen saturation ≤ 85% as measured by pulse oximetry during exercise testing at Visit 1, Visit 2 or Visit 3 prior to randomisation. 7. Patients with a Body Mass Index (BMI) ≥ 40kg/m2. 8. Patient who may need to start a pulmonary rehabilitation program during the study and/or who started/finished it within 3 months prior to Visit 1 or during the run-in period. 9. Patients with clinically significant cardiovascular conditions. 10. Patients with Type I or uncontrolled Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled or untreated hypertension. 11. Patient with known non-controlled history of infection with human immunodeficiency virus (HIV) and/or active hepatitis. 12. Patients with clinically relevant abnormalities in the results of the blood pressure, ECG, or physical examination at Visit 1. 13. Patients with any serious or uncontrolled physical or mental dysfunction that could place the patient at higher risk derived from his/her participation in the study or could confound the results 14. Patients with conditions other than COPD that may contribute to dyspnoea and exercise limitation or with contraindications to clinical exercise testing according to ATS recommendations for CPET 15. Patients with other relevant comorbidities that make the patient nor suitable to follow-up study procedures and/or could affect physical activity 16. Patients who cycled \< 2 minutes or \> 15 minutes during the constant work-rate exercise tests conducted at Visit 2 (Run-in Visit) or at Visit 3 even after adjustment of the work load. 17. Patients with history of hypersensitivity reaction to inhaled anticholinergics, sympathomimetic amines or inhaled medication or any component thereof (including report of paradoxical bronchospasm) 18. Patients for whom the use of anticholinergic drugs is contraindicated (acute urinary retention, symptomatic prostatic hypertrophy, bladder neck obstruction or narrow-angle glaucoma) 19. Patients unable to properly use a multidose dry powder inhaler or a pressurized metered-dose inhaler (pMDI). 20. Patients using any prohibited medication (including IMP within 30 days (or 6 half-lives, whichever is longer) before Visit 1) or who have not undergone the required washout period. 21. 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). 22. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers, sleep apnea). 23. Patients unable to give their consent, or patients of consenting age but under guardianship, or vulnerable patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough Functional Residual Capacity (FRC) After 4 Weeks of Treatment | Baseline and Week 4 | Baseline values in FRC were defined as the corresponding values just before randomization on Day 1 of treatment (Week 0). Trough values were obtained prior to study drug administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Endurance Time (ET) During Constant Work Rate Cycle Ergometry at Week 8 | Baseline to Week 8 | The ET was the time from the increase in work rate to 75% Wmax to the point of symptom limitation. Baseline measurements were taken prior to the IP dose on Day 1. Measurements at Week 8 were taken at 3 hours post-dose. Participants underwent a behavioural intervention (consisting of a telecoaching programme to enhance physical activity) between Week 4 and Week 8. |
| Percentage of Inactive Patients (Mean of <6000 Steps Per Day) at Week 8 | Week 8 | Physical activity was assessed by means of measurement of activity parameters (e.g. number of steps) through a Dynaport MoveMonitor and completion of the Daily ProActive Physical Activity in chronic obstructive pulmonary disease (COPD) questionnaire. Compliant criterion based on at least 8 hours per day, and at least 3 days per week. Participants underwent a behavioural intervention (consisting of a telecoaching programme to enhance physical activity) between Week 4 and Week 8. Baseline was defined as mean of steps/day assessed during the week before the randomisation visit. |
Countries
Canada, Germany, Hungary, Spain
Participant flow
Recruitment details
This study was conducted at 26 study centers, 15 in Germany, 4 in Hungary, 3 in Spain and 4 in Canada. The first patient was enrolled in April 2015 and the last patient visit was in July 2016.
Pre-assignment details
335 patients were screened; 267 were assessed as eligible and were randomized into the study. 68 patients failed screening. The main reason for screening failure was non-fulfilment of inclusion or exclusion criteria (16.7%).
Participants by arm
| Arm | Count |
|---|---|
| AB/FF 400/12 μg Aclidinium Bromide/Formoterol Fumarate 400/12 μg | 134 |
| Placebo Placebo to Aclidinium/Formoterol | 133 |
| Total | 267 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 8 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | AB/FF 400/12 μg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 62.6 Years STANDARD_DEVIATION 7.9 | 62.1 Years STANDARD_DEVIATION 7.7 | 62.3 Years STANDARD_DEVIATION 7.8 |
| Sex: Female, Male Female | 53 Participants | 54 Participants | 107 Participants |
| Sex: Female, Male Male | 81 Participants | 79 Participants | 160 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 134 | 24 / 133 |
| serious Total, serious adverse events | 2 / 134 | 3 / 133 |
Outcome results
Primary
Change From Baseline in Trough Functional Residual Capacity (FRC) After 4 Weeks of Treatment
Baseline values in FRC were defined as the corresponding values just before randomization on Day 1 of treatment (Week 0). Trough values were obtained prior to study drug administration.
Time frame: Baseline and Week 4
Population: The intent-to-treat (ITT) population - equal to the Safety population and defined as all randomised patients who took at least one dose of investigational product (IP) - who had available trough FRC values at baseline and Week 4.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in Trough Functional Residual Capacity (FRC) After 4 Weeks of Treatment | -0.162 Liters | Standard Error 0.05 |
| Placebo | Change From Baseline in Trough Functional Residual Capacity (FRC) After 4 Weeks of Treatment | -0.037 Liters | Standard Error 0.05 |
p-value: 0.06995% CI: [-0.259, 0.01]ANCOVA
Secondary
Change From Baseline in Endurance Time (ET) During Constant Work Rate Cycle Ergometry at Week 8
The ET was the time from the increase in work rate to 75% Wmax to the point of symptom limitation. Baseline measurements were taken prior to the IP dose on Day 1. Measurements at Week 8 were taken at 3 hours post-dose. Participants underwent a behavioural intervention (consisting of a telecoaching programme to enhance physical activity) between Week 4 and Week 8.
Time frame: Baseline to Week 8
Population: Intention-to-treat population - which was equal to the safety population, defined as all participants who took at least one dose of investigational product - who had available ET values at baseline and Week 8.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in Endurance Time (ET) During Constant Work Rate Cycle Ergometry at Week 8 | 50.7 Seconds | Standard Error 18.1 |
| Placebo | Change From Baseline in Endurance Time (ET) During Constant Work Rate Cycle Ergometry at Week 8 | -4.6 Seconds | Standard Error 18.2 |
Secondary
Percentage of Inactive Patients (Mean of <6000 Steps Per Day) at Week 8
Physical activity was assessed by means of measurement of activity parameters (e.g. number of steps) through a Dynaport MoveMonitor and completion of the Daily ProActive Physical Activity in chronic obstructive pulmonary disease (COPD) questionnaire. Compliant criterion based on at least 8 hours per day, and at least 3 days per week. Participants underwent a behavioural intervention (consisting of a telecoaching programme to enhance physical activity) between Week 4 and Week 8. Baseline was defined as mean of steps/day assessed during the week before the randomisation visit.
Time frame: Week 8
Population: The intent-to-treat (ITT) population - equal to the Safety population and defined as all randomised patients who took at least one dose of IP~\- who had available activity data (compliant criterion).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AB/FF 400/12 μg | Percentage of Inactive Patients (Mean of <6000 Steps Per Day) at Week 8 | 41.53 Percent of inactive participants |
| Placebo | Percentage of Inactive Patients (Mean of <6000 Steps Per Day) at Week 8 | 50.43 Percent of inactive participants |