Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
Chronic obstructive pulmonary disease, indacaterol, salmeterol, placebo controlled
Brief summary
This study evaluated the safety and efficacy of 26 weeks treatment with indacaterol, placebo or salmeterol in patients with chronic obstructive pulmonary disease.
Interventions
Indacaterol 150 μg once daily (o.d) inhaled
DRUGSalmeterol 50 μg
Salmeterol 50 μg twice daily (b.i.d) delivered via a proprietary dry powder inhaler
DRUGPlacebo to Indacaterol
Placebo to Indacaterol inhaled via SDDPI.
Placebo to salmeterol delivered via a proprietary dry powder inhaler
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Clinical diagnosis of moderate to severe Chronic Obstructive Pulmonary Disease (COPD) as per the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2006 Guidelines (mandatory) and including: * Smoking history of at least 20 pack years * Post-bronchodilator Forced Expiratory Volume in 1 second (FEV1) \< 80% predicted and \>or= 30% of predicted normal value * Post-bronchodilator FEV1/FVC \< 70% (Post defined as within 30 minutes of inhalation of 400 µg salbutamol)
Exclusion criteria
* Pregnant or nursing (lactating) women and women of child-bearing potential UNLESS they meet pre-specified definitions of post-menopausal or are using pre-specified acceptable methods of contraception * Hospitalisation for COPD exacerbation in the 6 weeks prior to Visit 1 or during run-in * Patients requiring oxygen therapy for chronic hypoxemia (typically \>15h/day) * Respiratory tract infection within 6 weeks prior to Visit 1 and during the run-in period * Concomitant pulmonary disease * Asthma history (eosinophils \> 400/mm3; symptoms prior to age 40). Includes history of childhood asthma * History of long QTc syndrome or QTc interval \> 450 ms for males and \>470 ms for females * Patients who have a clinically significant condition or a clinically relevant laboratory abnormality * History of reactions to sympathomimetic amines or inhaled medication * Inability to use the dry powder devices or perform spirometry * Irregular day/night, wake/sleep cycles, e.g. shift workers * Certain medications for COPD and allied conditions such as long acting bronchodilators must not be used prior to Visit 1 and for a pre-specified minimum washout period * Patients unable or unwilling to complete a patient diary Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough Forced Expiratory Volume in 1 Second (FEV1) After 12 Weeks 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, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 Weeks of Treatment | Week 12 | SGRQ is a health related quality of life questionnaire consisting of 76 items in three sections: symptoms, activity and impacts. The total score is 0 to 100 with a higher score indicating poorer health status. The mixed model used baseline SGRQ total score, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and one hour post inhalation of ipratropium as covariates. |
| Percentage of COPD Days of Poor Control During 26 Weeks of Treatment | Up to 26 weeks | Participants rated their symptoms on a scale of 0=none to 3=severe. A Chronic Obstructive Pulmonary Disease (COPD) day of poor control was defined as any day in the participants diary with a score \>=2 (moderate or severe) for at least 2 of 5 symptoms (cough, wheeze, production of sputum, color of sputum, breathlessness). The mixed model used baseline percentage of days of poor control, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and one hour post inhalation of ipratropium as covariates. |
Countries
Canada, Colombia, Czechia, Denmark, Finland, France, Germany, Hungary, Iceland, India, Italy, Peru, Russia, Slovakia, Taiwan
Participant flow
Pre-assignment details
1002 participants were randomized. 3 randomized participants in the Indacaterol group and 1 randomized participant in the Salmeterol group did not receive study medication and were not included in the intent-to-treat milestone.
Participants by arm
| Arm | Count |
|---|---|
| Indacaterol 150 μg Indacaterol 150 μg once daily in the morning, inhaled via a single dose dry powder inhaler (SDDPI). Placebo to Salmeterol delivered twice daily via a proprietary dry powder inhaler in the morning and in the evening. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) salbutamol/albuterol was available for rescue use throughout the study. | 330 |
| Salmeterol 50 μg Salmeterol 50 μg twice daily delivered via a proprietary dry powder inhaler in the morning and in the evening. Placebo to Indacaterol daily in the morning, inhaled via a single dose dry powder inhaler (SDDPI). Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) salbutamol/albuterol was available for rescue use throughout the study. | 333 |
| Placebo Placebo to indacaterol inhaled via SDDPI. Placebo to salmeterol delivered twice daily via a proprietary dry powder inhaler in the morning and in the evening. Daily inhaled corticosteroid treatment (if applicable) was allowed to remain stable throughout the study. The short acting (beta) β2-agonist (SABA) salbutamol/albuterol was available for rescue use throughout the study. | 335 |
| Total | 998 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Abnormal Lab value(s) | 2 | 1 | 2 |
| Overall Study | Abnormal test procedure result(s) | 2 | 1 | 1 |
| Overall Study | Administrative problems | 1 | 1 | 0 |
| Overall Study | Adverse Event | 18 | 16 | 13 |
| Overall Study | Death | 1 | 0 | 2 |
| Overall Study | Lost to Follow-up | 2 | 5 | 2 |
| Overall Study | Patient's inability to use the device | 0 | 1 | 0 |
| Overall Study | Protocol Deviation | 9 | 11 | 13 |
| Overall Study | Unsatisfactory therapeutic effect | 1 | 2 | 15 |
| Overall Study | Withdrawal by Subject | 8 | 12 | 22 |
Baseline characteristics
| Characteristic | Indacaterol 150 μg | Salmeterol 50 μg | Placebo | Total |
|---|---|---|---|---|
| Age Continuous | 63.2 years STANDARD_DEVIATION 8.67 | 63.4 years STANDARD_DEVIATION 9.19 | 63.9 years STANDARD_DEVIATION 8.56 | 63.5 years STANDARD_DEVIATION 8.81 |
| Sex: Female, Male Female | 92 Participants | 84 Participants | 77 Participants | 253 Participants |
| Sex: Female, Male Male | 238 Participants | 249 Participants | 258 Participants | 745 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 69 / 330 | 68 / 333 | 71 / 335 |
| serious Total, serious adverse events | 29 / 330 | 19 / 333 | 26 / 335 |
Outcome results
Primary
Trough Forced Expiratory Volume in 1 Second (FEV1) After 12 Weeks of Treatment
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, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates.
Time frame: Week 12
Population: Intent-to-treat population included all randomized participants who received at least one dose of study medication. The end point was analyzed only for those participants who had Trough FEV1 data at week 12. Missing data were imputed using Last Observation carried Forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 μg | Trough Forced Expiratory Volume in 1 Second (FEV1) After 12 Weeks of Treatment | 1.45 Liters | Standard Error 0.018 |
| Salmeterol 50 μg | Trough Forced Expiratory Volume in 1 Second (FEV1) After 12 Weeks of Treatment | 1.39 Liters | Standard Error 0.018 |
| Placebo | Trough Forced Expiratory Volume in 1 Second (FEV1) After 12 Weeks of Treatment | 1.28 Liters | Standard Error 0.019 |
Secondary
Percentage of COPD Days of Poor Control During 26 Weeks of Treatment
Participants rated their symptoms on a scale of 0=none to 3=severe. A Chronic Obstructive Pulmonary Disease (COPD) day of poor control was defined as any day in the participants diary with a score \>=2 (moderate or severe) for at least 2 of 5 symptoms (cough, wheeze, production of sputum, color of sputum, breathlessness). The mixed model used baseline percentage of days of poor control, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and one hour post inhalation of ipratropium as covariates.
Time frame: Up to 26 weeks
Population: Intent-to-treat population included all randomized 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 COPD Days of Poor Control During 26 Weeks of Treatment | 34.1 Percentage of days | Standard Error 1.82 |
| Salmeterol 50 μg | Percentage of COPD Days of Poor Control During 26 Weeks of Treatment | 34.1 Percentage of days | Standard Error 1.82 |
| Placebo | Percentage of COPD Days of Poor Control During 26 Weeks of Treatment | 38.1 Percentage of days | Standard Error 1.85 |
Secondary
St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 Weeks of Treatment
SGRQ is a health related quality of life questionnaire consisting of 76 items in three sections: symptoms, activity and impacts. The total score is 0 to 100 with a higher score indicating poorer health status. The mixed model used baseline SGRQ total score, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and one hour post inhalation of ipratropium as covariates.
Time frame: Week 12
Population: Intent-to-treat population included all randomized participants who received at least one dose of study medication. The endpoint was analyzed only for those participants who had SGRQ data at week 12. Missing data were imputed using Last Observation carried Forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 μg | St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 Weeks of Treatment | 36.4 Score on a scale | Standard Error 1.04 |
| Salmeterol 50 μg | St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 Weeks of Treatment | 38.5 Score on a scale | Standard Error 1.04 |
| Placebo | St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 Weeks of Treatment | 42.6 Score on a scale | Standard Error 1.05 |