Chronic Obstructive Pulmonary Disease
Conditions
Keywords
chronic obstructive pulmonary disease, COPD, indacaterol, long-acting β2 agonist
Brief summary
This study was designed to assess the efficacy and long-term safety of 300 and 600 µg doses of indacaterol when delivered via a single-dose dry-powder inhaler (SDDPI) in patients with chronic obstructive pulmonary disease (COPD). Patients were randomized to receive either indacaterol 300 µg once daily, indacaterol 600 µg once daily, formoterol 12 µg twice daily, or placebo.
Interventions
DRUGIndacaterol
Indacaterol was supplied in powder-filled capsules with a single-dose dry-powder inhaler (SDDPI).
DRUGFormoterol
Formoterol was supplied in powder-filled capsules with the manufacturer's proprietary inhalation device (Aerolizer®).
DRUGPlacebo to indacaterol
Placebo to indacaterol was supplied in powder-filled capsules with a single-dose dry-powder inhaler (SDDPI).
Placebo to formoterol was supplied in powder-filled capsules with the manufacturer's proprietary inhalation device (Aerolizer®).
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female adults ≥ 40 years, with a diagnosis of chronic obstructive pulmonary disease (COPD) according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines 2005 and: 1. Smoking history of at least 20 pack years 2. Post-bronchodilator forced expiratory volume in 1 second (FEV1) \< 80% and ≥ 30% of the predicted normal value 3. Post-bronchodilator FEV1/FVC (forced volume capacity) \< 70% (Post refers to within 30 minutes after inhalation of 400 μg of salbutamol)
Exclusion criteria
* Patients who were hospitalized for a COPD exacerbation in the 6 weeks prior to screening. * Patients who had a respiratory tract infection within 6 weeks prior to screening. * Patients with concomitant pulmonary disease. * Patients with a history of asthma. * Patients with diabetes type I or uncontrolled diabetes type II. * Any patient with lung cancer or a history of lung cancer. * Patients with a history of certain cardiovascular co-morbid conditions. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 + 1 Day, Day 85 | Week 12 + 1 day, Day 85 | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes post-dose at the end of treatment. The analysis included baseline FEV1, FEV1 pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Days of Poor Control During 52 Weeks of Treatment | Baseline to end of study (Week 52) | Percentage of days of poor control was defined as the number of days in the patient diary with a score ≥ 2 (scale of 0-3, a higher number means more severe symptoms) for at least 2 of 5 symptoms (cough, wheeze, production of sputum, color of sputum, breathlessness) over 52 weeks divided by the number of evaluable days (days with ≥ 2 symptoms with scores). The analysis included baseline percentage of days of poor control, FEV1 pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates. |
Countries
Argentina, Chile, Colombia, Czechia, Denmark, Ecuador, Egypt, Estonia, France, Germany, Hungary, Israel, Italy, Latvia, Lithuania, Netherlands, Peru, Romania, Russia, Slovakia, South Korea, Spain, Switzerland, Turkey (Türkiye), United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Indacaterol 300 μg Plus Placebo to Formoterol Patients inhaled indacaterol 300 μg once daily via a single-dose dry-powder inhaler (SDDPI), placebo to indacaterol once daily via a SDDPI, and placebo to formoterol twice daily via the manufacturer's proprietary inhalation device (Aerolizer®). Indacaterol, placebo to indacaterol, and placebo to formoterol were taken in the morning between 8:00 and 10:00 AM; placebo to formoterol was taken again 12 hours later in the evening between 8:00 and 10:00 PM. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | 437 |
| Indacaterol 600 μg Plus Placebo to Formoterol Patients inhaled indacaterol 600 μg (two 300 μg capsules) once daily via single-dose dry-powder inhalers (SDDPI) plus placebo to formoterol twice daily via the manufacturer's proprietary inhalation device (Aerolizer®). Indacaterol and placebo to formoterol were taken in the morning between 8:00 and 10:00 AM; placebo to formoterol was taken again 12 hours later in the evening between 8:00 and 10:00 PM. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | 425 |
| Formoterol 12 μg Plus Placebo to Indacaterol Patients inhaled formoterol 12 μg twice daily via the manufacturer's proprietary inhalation device (Aerolizer®) plus placebo to indacaterol once daily via a single-dose dry-powder inhaler (SDDPI). Formoterol and placebo to indacaterol were taken in the morning between 8:00 and 10:00 AM; formoterol was taken again 12 hours later in the evening between 8:00 and 10:00 PM. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | 434 |
| Placebo to Indacaterol Plus Placebo to Formoterol Patients inhaled placebo to indacaterol once daily via a single-dose dry-powder inhaler (SDDPI) plus placebo to formoterol twice daily via the manufacturer's proprietary inhalation device (Aerolizer®). Placebo to indacaterol and placebo to formoterol were taken in the morning between 8:00 and 10:00 AM; placebo to formoterol was taken again 12 hours later in the evening between 8:00 and 10:00 PM. Daily inhaled corticosteroid treatment (if applicable) was to remain stable throughout the study. The short-acting β2-agonist salbutamol/albuterol was available for rescue use throughout the study. | 432 |
| Total | 1,728 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 1 | 1 | 0 | 0 |
| Overall Study | Abnormal test procedure result(s) | 0 | 1 | 1 | 2 |
| Overall Study | Administrative problems | 7 | 8 | 5 | 2 |
| Overall Study | Adverse Event | 35 | 24 | 40 | 35 |
| Overall Study | Death | 1 | 1 | 5 | 5 |
| Overall Study | Lost to Follow-up | 5 | 6 | 5 | 3 |
| Overall Study | Protocol deviation | 11 | 11 | 11 | 10 |
| Overall Study | Subject no longer requires study drug | 0 | 1 | 0 | 0 |
| Overall Study | Subject withdrew consent | 27 | 40 | 33 | 50 |
| Overall Study | Unsatisfactory therapeutic effect | 12 | 9 | 12 | 30 |
Baseline characteristics
| Characteristic | Indacaterol 300 μg Plus Placebo to Formoterol | Indacaterol 600 μg Plus Placebo to Formoterol | Formoterol 12 μg Plus Placebo to Indacaterol | Placebo to Indacaterol Plus Placebo to Formoterol | Total |
|---|---|---|---|---|---|
| Age Continuous | 63.9 years STANDARD_DEVIATION 8.57 | 62.9 years STANDARD_DEVIATION 8.74 | 63.6 years STANDARD_DEVIATION 8.49 | 63.2 years STANDARD_DEVIATION 8.28 | 63.4 years STANDARD_DEVIATION 8.52 |
| Sex: Female, Male Female | 86 Participants | 98 Participants | 86 Participants | 80 Participants | 350 Participants |
| Sex: Female, Male Male | 351 Participants | 327 Participants | 348 Participants | 352 Participants | 1378 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 199 / 437 | 183 / 425 | 164 / 434 | 176 / 432 |
| serious Total, serious adverse events | 63 / 437 | 51 / 425 | 69 / 434 | 48 / 432 |
Outcome results
Primary
Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 + 1 Day, Day 85
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of measurements made 23 hours 10 minutes and 23 hours 45 minutes post-dose at the end of treatment. The analysis included baseline FEV1, FEV1 pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates.
Time frame: Week 12 + 1 day, Day 85
Population: Modified intent-to-treat (ITT) population: All randomized patients who received at least 1 dose of study drug, excluding patients from a number of centers.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 300 μg Plus Placebo to Formoterol | Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 + 1 Day, Day 85 | 1.48 Liters | Standard Error 0.012 |
| Indacaterol 600 μg Plus Placebo to Formoterol | Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 + 1 Day, Day 85 | 1.48 Liters | Standard Error 0.013 |
| Formoterol 12 μg Plus Placebo to Indacaterol | Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 + 1 Day, Day 85 | 1.38 Liters | Standard Error 0.013 |
| Placebo to Indacaterol Plus Placebo to Formoterol | Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 + 1 Day, Day 85 | 1.31 Liters | Standard Error 0.013 |
Secondary
Percentage of Days of Poor Control During 52 Weeks of Treatment
Percentage of days of poor control was defined as the number of days in the patient diary with a score ≥ 2 (scale of 0-3, a higher number means more severe symptoms) for at least 2 of 5 symptoms (cough, wheeze, production of sputum, color of sputum, breathlessness) over 52 weeks divided by the number of evaluable days (days with ≥ 2 symptoms with scores). The analysis included baseline percentage of days of poor control, FEV1 pre-dose and 30 minutes post-dose of salbutamol/albuterol during screening, and FEV1 pre-dose and 1 hour post-dose of ipratropium during screening as covariates.
Time frame: Baseline to end of study (Week 52)
Population: Modified intent-to-treat (ITT) population: All randomized patients who received at least 1 dose of study drug, excluding patients from a number of centers.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 300 μg Plus Placebo to Formoterol | Percentage of Days of Poor Control During 52 Weeks of Treatment | 33.6 Percentage of days | Standard Error 1.43 |
| Indacaterol 600 μg Plus Placebo to Formoterol | Percentage of Days of Poor Control During 52 Weeks of Treatment | 30.0 Percentage of days | Standard Error 1.46 |
| Formoterol 12 μg Plus Placebo to Indacaterol | Percentage of Days of Poor Control During 52 Weeks of Treatment | 33.5 Percentage of days | Standard Error 1.45 |
| Placebo to Indacaterol Plus Placebo to Formoterol | Percentage of Days of Poor Control During 52 Weeks of Treatment | 38.3 Percentage of days | Standard Error 1.47 |