Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Indacaterol, Tiotropium, COPD
Brief summary
This study compares indacaterol with tiotropium in terms of bronchodilation over 52 weeks
Interventions
Indacaterol 150 µg o.d. delivered via SDDPI
DRUGTiotropium
Tiotropium 18 µg o.d. delivered via handihaler®
Sponsors
Novartis Pharmaceuticals
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 aged ≥40 years, who have signed an Informed Consent form prior to initiation of any study-related procedure * Patients diagnosed with COPD at age 40 and over and with a current diagnosis of severe COPD and including: 1. Smoking history of at least 10 pack years, both current and ex-smokers are eligible 2. A documented history of at least 1 moderate or severe exacerbation in the previous 12 months
Exclusion criteria
* Patients who have received systemic corticosteroids and/or antibiotics for a COPD exacerbation in the 6 weeks prior to screening or during the run-in period * Patients who have 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 comorbid conditions Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough Forced Expiratory Volume in 1 Second (FEV1). | 12 weeks | The primary objective of the study was to demonstrate the non-inferiority of indacaterol vs. tiotropium with respect to 24 hour post dose (trough) FEV1 after 12 weeks of treatment in patients with severe COPD. Trough FEV1 was defined as the average of the 23 hours 10 min and the 23 hours 45 min post dose values. Trough FEV1 was analyzed using a mixed model for the PPS-S. The model contained treatment as a fixed effect with the baseline FEV1, FEV1 prior to inhalation and FEV1 15 min post-inhalation of salbutamol/albuterol (components of SABA reversibility at Visit 2), FEV1 prior to inhalation and FEV1 60 min post-inhalation of ipratropium (components of anti-cholinergic reversibility at Visit 3) as covariates. Smoking history (current or ex-smoker) was included as a factor in the model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of COPD Exacerbations | 52 weeks | COPD exacerbations were defined as :Worsening of 2 or more major symptoms for at least 2 consecutive days: dyspnea; sputum volume; suputum purulence AND requiring treatment with systemic corticosteroids and/or antibiotics OR Worsening of any 1 major symptom together with any 1 of the following minor symptoms for at least 2 consecutive days: Sore throat; colds; fever without other cause; increased cough; increase wheeze AND requiring treatment with systemic glucocorticosteroids and/or antibiotics. The rate was analyzed using a linear model assuming a negative binomial distribution for the PPS-E. The time at risk for a patient was defined as the length of time the patient was in the study and the log(length of time in the study) was used as the offset variable in the model. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Colombia, Costa Rica, Czechia, Denmark, Estonia, Finland, France, Germany, Hungary, Iceland, India, Israel, Italy, Latvia, Lithuania, Mexico, Netherlands, Peru, Philippines, Poland, Portugal, Romania, Russia, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, Venezuela
Participant flow
Recruitment details
3,444 patients were randomized, but only 3,439 received treatment as 5 patients were mis-randomized.
Participants by arm
| Arm | Count |
|---|---|
| Indacaterol Indacaterol 150 μg o.d., delivered via SDDPI o.d. plus placebo to tiotropium o.d.
delivered via the manufacturer's proprietary inhalation device (Handihaler®) | 1,721 |
| Tiotropium Tiotropium 18 μg o.d. delivered via the manufacturer's proprietary inhalation device (Handihaler®) plus placebo to indacaterol o.d. delivered via SDDPI | 1,718 |
| Total | 3,439 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value (s) | 2 | 2 |
| Overall Study | Abnormal test procedure result (s) | 7 | 2 |
| Overall Study | Administrative Problems | 34 | 26 |
| Overall Study | Adverse Event | 101 | 96 |
| Overall Study | Death | 24 | 26 |
| Overall Study | Lack of Efficacy | 51 | 39 |
| Overall Study | Lost to Follow-up | 22 | 13 |
| Overall Study | Patient's inability to use the device | 4 | 6 |
| Overall Study | Protocol Violation | 36 | 24 |
| Overall Study | Withdrawal by Subject | 105 | 108 |
Baseline characteristics
| Characteristic | Indacaterol | Tiotropium | Total |
|---|---|---|---|
| Age, Customized <65 years | 929 Participants | 909 Participants | 1838 Participants |
| Age, Customized ≥ 65 years | 792 Participants | 809 Participants | 1601 Participants |
| Sex: Female, Male Female | 377 Participants | 405 Participants | 782 Participants |
| Sex: Female, Male Male | 1344 Participants | 1313 Participants | 2657 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 890 / 1,721 | 793 / 1,718 |
| serious Total, serious adverse events | 263 / 1,721 | 255 / 1,718 |
Outcome results
Primary
Trough Forced Expiratory Volume in 1 Second (FEV1).
The primary objective of the study was to demonstrate the non-inferiority of indacaterol vs. tiotropium with respect to 24 hour post dose (trough) FEV1 after 12 weeks of treatment in patients with severe COPD. Trough FEV1 was defined as the average of the 23 hours 10 min and the 23 hours 45 min post dose values. Trough FEV1 was analyzed using a mixed model for the PPS-S. The model contained treatment as a fixed effect with the baseline FEV1, FEV1 prior to inhalation and FEV1 15 min post-inhalation of salbutamol/albuterol (components of SABA reversibility at Visit 2), FEV1 prior to inhalation and FEV1 60 min post-inhalation of ipratropium (components of anti-cholinergic reversibility at Visit 3) as covariates. Smoking history (current or ex-smoker) was included as a factor in the model.
Time frame: 12 weeks
Population: Per-Protocol Set for Spirometry (PPS-S) This set included Full Analysis Set (FAS) patients without any major protocol deviations or non-protocol deviation criteria that could affect the respective analysis of efficacy.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol | Trough Forced Expiratory Volume in 1 Second (FEV1). | 1.134 Liters | Standard Error 0.0008 |
| Tiotropium | Trough Forced Expiratory Volume in 1 Second (FEV1). | 1.145 Liters | Standard Error 0.0008 |
Secondary
Rate of COPD Exacerbations
COPD exacerbations were defined as :Worsening of 2 or more major symptoms for at least 2 consecutive days: dyspnea; sputum volume; suputum purulence AND requiring treatment with systemic corticosteroids and/or antibiotics OR Worsening of any 1 major symptom together with any 1 of the following minor symptoms for at least 2 consecutive days: Sore throat; colds; fever without other cause; increased cough; increase wheeze AND requiring treatment with systemic glucocorticosteroids and/or antibiotics. The rate was analyzed using a linear model assuming a negative binomial distribution for the PPS-E. The time at risk for a patient was defined as the length of time the patient was in the study and the log(length of time in the study) was used as the offset variable in the model.
Time frame: 52 weeks
Population: Per-Protocol Set for Exacerbations (PPS-E). This set included Full Analysis Set (FAS) patients without any major protocol deviations or non-protocol deviation criteria that could affect the respective analysis of efficacy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Indacaterol | Rate of COPD Exacerbations | 0.79 Exacerbations per patient per year |
| Tiotropium | Rate of COPD Exacerbations | 0.61 Exacerbations per patient per year |