Chronic Obstructive Pulmonary Disease
Conditions
Keywords
COPD, indacaterol, beta 2 agonist, tiotropium
Brief summary
This study compared the lung effects of indacaterol to those of tiotropium in patients with moderate to severe chronic obstructive pulmonary disease (COPD) over a 12 week period.
Interventions
Indacaterol 150 μg was provided in powder filled capsules with a single dose dry powder inhaler (SDDPI).
DRUGTiotropium 18 μg
Tiotropium 18 μg was provided in powder filled capsules with the manufacturer's proprietary inhalation device (HandiHaler®).
DRUGPlacebo to indacaterol
Placebo to indacaterol was provided in powder filled capsules with a single dose dry powder inhaler (SDDPI).
Placebo to tiotropium was provided in powder filled capsules with the manufacturer's proprietary inhalation device (HandiHaler®).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Diagnosis of COPD (moderate-to-severe as classified by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, 2007) and: * a) Smoking history of at least 10 pack-years * b) Post-bronchodilator forced expiratory volume in 1 second (FEV1) \< 80% and ≥ 30% of the predicted normal value * c) Post-bronchodilator FEV1/FVC (forced vital capacity) \< 70%
Exclusion criteria
* Patients who have received systemic corticosteroids or antibiotics and/or was hospitalized for a COPD exacerbation in the 6 weeks prior to screening * 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) at End of Treatment (Week 12) | End of treatment (Week 12) | Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 hour 10 minute and 23 hour 45 minute post-dose FEV1 readings. Mixed model used baseline FEV1, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Transition Dyspnea Index (TDI) Focal Score After 12 Weeks of Treatment | 12 weeks | TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. Each domain is scored from -3 (major deterioration) to 3 (major improvement) to give an overall TDI focal score of -9 to 9 with a negative score indicating a deterioration from baseline. A 1 unit difference in the TDI focal score is clinically significant. Mixed model used baseline dyspnea index, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. |
| Quality of Life Assessment With St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 Weeks of Treatment | 12 weeks | SGRQ is a health related quality of life questionnaire consisting of 50 items in three domains: symptoms (frequency and severity), activity (that cause or are limited by breathlessness) and impacts (social functioning & psychological disturbances resulting from airway disease). The total score is 0 to 100 with a higher score indicating greater impairment of health status. Mixed model used baseline SGRQ, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. |
| Change From Baseline in the Mean Number of Puffs Per Day of Rescue Medication Over the Study Duration (From Day 1 to Week 12) | Baseline, up to 12 weeks | Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each morning and evening in an electronic diary. The number of puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of puffs of rescue medication for each participant. Mixed model used baseline number of puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. |
| Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours Post-dose at the End of Treatment (Week 12) | 5 minutes to 4 hours post-dose at the end of treatment (week 12) | Spirometry was conducted according to internationally accepted standards. FEV1 was measured at 5 and 30 minutes; and 1, 2, and 4 hours post-dose on Week 12. Standardized FEV1 AUC (5 minutes-4 hour) post-dose at week 12 was calculated based on the trapezoidal rule, and was adjusted for the area per time unit by using the scheduled time of measurements for FEV1. Mixed model used baseline FEV1, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. |
| Change From Baseline in the Mean Number Per Day of Nighttime Puffs of Rescue Medication Over the Study Duration (From Day 1 to Week 12) | Baseline, up to 12 weeks | Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each morning in an electronic diary. The number of nighttime puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of nighttime puffs of rescue medication for each participant. Mixed model used baseline number of nighttime puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. |
| Percentage of Days With no Rescue Medication Use During the 12 Weeks of Treatment | Up to 12 weeks | A day with no rescue medication was defined as any day in the diary that the participant used no puffs of rescue medication. The percentage of days with no rescue medication was calculated by dividing the number of days with no rescue medication over the 12 week treatment period by the number of evaluable days and multiplying by 100. Mixed model used baseline percentage of days with no rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. |
| Change From Baseline in the Mean Number Per Day of Daytime Puffs of Rescue Medication Over the Study Duration (From Day 1 to Week 12) | Baseline, up to 12 weeks | Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each evening in an electronic diary. The number of daytime puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of daytime puffs of rescue medication for each participant. Mixed model used baseline number of daytime puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates. |
Countries
Austria, Belgium, Canada, Colombia, Denmark, Finland, France, Germany, Greece, Hungary, Israel, Italy, Mexico, Norway, Poland, Russia, Slovakia, Spain, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
1598 participants were randomized. 3 participants in the Indacaterol group and 2 participants in the Tiotropium group did not receive study medication.
Participants by arm
| Arm | Count |
|---|---|
| Indacaterol 150 µg Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication. | 794 |
| Tiotropium 18 µg Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication. | 799 |
| Total | 1,593 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal Laboratory Value(s) | 2 | 4 |
| Overall Study | Abnormal Test Procedure Result(s) | 3 | 0 |
| Overall Study | Administrative Problems | 5 | 4 |
| Overall Study | Adverse Event | 31 | 27 |
| Overall Study | Death | 0 | 2 |
| Overall Study | Lack of Efficacy | 1 | 3 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Protocol Deviation | 8 | 11 |
| Overall Study | Withdrawal by Subject | 8 | 7 |
Baseline characteristics
| Characteristic | Indacaterol 150 µg | Tiotropium 18 µg | Total |
|---|---|---|---|
| Age Continuous | 63.6 years STANDARD_DEVIATION 8.6 | 63.4 years STANDARD_DEVIATION 8.29 | 63.5 years STANDARD_DEVIATION 8.45 |
| Sex: Female, Male Female | 239 Participants | 261 Participants | 500 Participants |
| Sex: Female, Male Male | 555 Participants | 538 Participants | 1093 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 80 / 794 | 61 / 799 |
| serious Total, serious adverse events | 22 / 794 | 30 / 799 |
Outcome results
Primary
Trough Forced Expiratory Volume in 1 Second (FEV1) at End of Treatment (Week 12)
Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 hour 10 minute and 23 hour 45 minute post-dose FEV1 readings. Mixed model used baseline FEV1, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.
Time frame: End of treatment (Week 12)
Population: Per-protocol population included all participants who received at least one dose of study medication without any major protocol deviations. The endpoint was analyzed only for those participants who had data for this outcome measure. Missing data were imputed using last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg | Trough Forced Expiratory Volume in 1 Second (FEV1) at End of Treatment (Week 12) | 1.44 Liters | Standard Error 0.01 |
| Tiotropium 18 µg | Trough Forced Expiratory Volume in 1 Second (FEV1) at End of Treatment (Week 12) | 1.43 Liters | Standard Error 0.01 |
Secondary
Change From Baseline in the Mean Number of Puffs Per Day of Rescue Medication Over the Study Duration (From Day 1 to Week 12)
Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each morning and evening in an electronic diary. The number of puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of puffs of rescue medication for each participant. Mixed model used baseline number of puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.
Time frame: Baseline, up to 12 weeks
Population: Full analysis set included all participants who received at least 1 dose of study medication. The endpoint was analyzed only for those participants who had data at baseline and at week 12 for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg | Change From Baseline in the Mean Number of Puffs Per Day of Rescue Medication Over the Study Duration (From Day 1 to Week 12) | -1.40 Puffs | Standard Error 0.097 |
| Tiotropium 18 µg | Change From Baseline in the Mean Number of Puffs Per Day of Rescue Medication Over the Study Duration (From Day 1 to Week 12) | -0.85 Puffs | Standard Error 0.097 |
Secondary
Change From Baseline in the Mean Number Per Day of Daytime Puffs of Rescue Medication Over the Study Duration (From Day 1 to Week 12)
Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each evening in an electronic diary. The number of daytime puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of daytime puffs of rescue medication for each participant. Mixed model used baseline number of daytime puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.
Time frame: Baseline, up to 12 weeks
Population: Full analysis set included all participants who received at least 1 dose of study medication. The endpoint was analyzed only for those participants who had data at baseline and at week 12 for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg | Change From Baseline in the Mean Number Per Day of Daytime Puffs of Rescue Medication Over the Study Duration (From Day 1 to Week 12) | -0.90 Puffs | Standard Error 0.063 |
| Tiotropium 18 µg | Change From Baseline in the Mean Number Per Day of Daytime Puffs of Rescue Medication Over the Study Duration (From Day 1 to Week 12) | -0.59 Puffs | Standard Error 0.063 |
Secondary
Change From Baseline in the Mean Number Per Day of Nighttime Puffs of Rescue Medication Over the Study Duration (From Day 1 to Week 12)
Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each morning in an electronic diary. The number of nighttime puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of nighttime puffs of rescue medication for each participant. Mixed model used baseline number of nighttime puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.
Time frame: Baseline, up to 12 weeks
Population: Full analysis set included all participants who received at least 1 dose of study medication. The endpoint was analyzed only for those participants who had data at baseline and at week 12 for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg | Change From Baseline in the Mean Number Per Day of Nighttime Puffs of Rescue Medication Over the Study Duration (From Day 1 to Week 12) | -0.52 Puffs | Standard Error 0.043 |
| Tiotropium 18 µg | Change From Baseline in the Mean Number Per Day of Nighttime Puffs of Rescue Medication Over the Study Duration (From Day 1 to Week 12) | -0.28 Puffs | Standard Error 0.042 |
Secondary
Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours Post-dose at the End of Treatment (Week 12)
Spirometry was conducted according to internationally accepted standards. FEV1 was measured at 5 and 30 minutes; and 1, 2, and 4 hours post-dose on Week 12. Standardized FEV1 AUC (5 minutes-4 hour) post-dose at week 12 was calculated based on the trapezoidal rule, and was adjusted for the area per time unit by using the scheduled time of measurements for FEV1. Mixed model used baseline FEV1, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.
Time frame: 5 minutes to 4 hours post-dose at the end of treatment (week 12)
Population: Full analysis set included all participants who received at least one dose of study medication. The endpoint was analyzed only for those participants who had data at week 12 for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg | Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours Post-dose at the End of Treatment (Week 12) | 1.51 Liter | Standard Error 0.01 |
| Tiotropium 18 µg | Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours Post-dose at the End of Treatment (Week 12) | 1.52 Liter | Standard Error 0.01 |
Secondary
Percentage of Days With no Rescue Medication Use During the 12 Weeks of Treatment
A day with no rescue medication was defined as any day in the diary that the participant used no puffs of rescue medication. The percentage of days with no rescue medication was calculated by dividing the number of days with no rescue medication over the 12 week treatment period by the number of evaluable days and multiplying by 100. Mixed model used baseline percentage of days with no rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.
Time frame: Up to 12 weeks
Population: Full analysis set included all participants who received at least one dose of study medication. The endpoint was analyzed only for those participants who had data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg | Percentage of Days With no Rescue Medication Use During the 12 Weeks of Treatment | 46.1 Percentage of days | Standard Error 1.65 |
| Tiotropium 18 µg | Percentage of Days With no Rescue Medication Use During the 12 Weeks of Treatment | 41.4 Percentage of days | Standard Error 1.64 |
Secondary
Quality of Life Assessment With St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 Weeks of Treatment
SGRQ is a health related quality of life questionnaire consisting of 50 items in three domains: symptoms (frequency and severity), activity (that cause or are limited by breathlessness) and impacts (social functioning & psychological disturbances resulting from airway disease). The total score is 0 to 100 with a higher score indicating greater impairment of health status. Mixed model used baseline SGRQ, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.
Time frame: 12 weeks
Population: Full Analysis Set included all randomized participants who received at least one dose of study drug. The endpoint was analyzed only for those participants who had data at week 12 for this outcome measure. Missing data were imputed using Last Observation Carried Forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg | Quality of Life Assessment With St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 Weeks of Treatment | 37.1 Score on a scale | Standard Error 0.56 |
| Tiotropium 18 µg | Quality of Life Assessment With St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 Weeks of Treatment | 39.2 Score on a scale | Standard Error 0.55 |
Secondary
Transition Dyspnea Index (TDI) Focal Score After 12 Weeks of Treatment
TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. Each domain is scored from -3 (major deterioration) to 3 (major improvement) to give an overall TDI focal score of -9 to 9 with a negative score indicating a deterioration from baseline. A 1 unit difference in the TDI focal score is clinically significant. Mixed model used baseline dyspnea index, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.
Time frame: 12 weeks
Population: Full Analysis Set included all randomized participants who received at least one dose of study drug. The endpoint was analyzed only for those participants who had data at week 12 for this outcome measure. Missing data were imputed using Last Observation Carried Forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg | Transition Dyspnea Index (TDI) Focal Score After 12 Weeks of Treatment | 2.01 Score on a scale | Standard Error 0.178 |
| Tiotropium 18 µg | Transition Dyspnea Index (TDI) Focal Score After 12 Weeks of Treatment | 1.43 Score on a scale | Standard Error 0.178 |