Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
COPD, QVA149
Brief summary
This study will evaluate the efficacy and safety of QVA149 (110/50 μg o.d.) vs tiotropium (18 µg o.d.) + salmeterol/fluticasone propionate FDC (50/500 µg b.i.d.) in patients with moderate to severe COPD
Interventions
DRUGQVA149
QVA149 will be supplied in a capsule form in blister packs for use in the Novartis Concept 1 SDDPI
DRUGTiotropium
Tiotropium will be supplied as commercially available blisters, delivered via HandiHaler®
Salmeterol/fluticasone propionate dry inhalation powder delivered via Accuhaler™
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
* Patients who have signed Informed Consent Form prior to initiation of any study-related procedure. * Male and female adults aged ≥ 40 years. * Patients with moderate to severe airflow obstruction with stable COPD (Stage 2 or Stage 3) according to the 2014 GOLD Guidelines. * Patients with a post-bronchodilator FEV1 ≥40 and \< 80% of the predicted normal value, and post-bronchodilator FEV1/FVC \< 0.70 at run-in Visit 101. (Post refers to 15 min after inhalation of 400 µg of salbutamol). * Current or ex-smokers who have a smoking history of at least 10 pack years (e.g. 10 pack years = 1 pack /day x 10 years, or ½ pack/day x 20 years). An ex-smoker is defined as a patient who has not smoked for ≥ 6 months at screening. * Patients who are on triple treatment at least for the last 6 months (LAMA +LABA/ICS).
Exclusion criteria
* Patients who have not achieved acceptable spirometry results at Visit 101 in accordance with ATS (American Thoracic Society)/ERS (European Respiratory Society) criteria for acceptability (one retest may be performed for patients that don't meet the acceptability criteria) . * Patients who have had more than one COPD exacerbation that required treatment with antibiotics and/or oral corticosteroids and/or hospitalization in the last year prior to Visit 1. * Patients who developed a COPD exacerbation of any severity either 6 weeks before the screening (Visit 1) or between screening (Visit 1) and treatment (Visit 201) will not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Post-dose Trough FEV1 | Baseline, 26 weeks | Mean change from baseline in post-dose trough forced expiratory volume in 1 second (FEV1) following 26 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values measured at 23 hr 15 min and 23 hr 45 min after the morning dose taken at site on Day 181. Baseline FEV1 is defined as the average of the pre-dose FEV1 measured at -45 min and -15 min at Day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of COPD Exacerbations Requiring Treatment With Systemic Glucocorticosteroids and/or Antibiotics, Moderate Exacerbations Only | 26 weeks | COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event |
| Annualized Rate of COPD Exacerbations Requiring Hospitalisation | 26 weeks | COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event. |
| Mean Change From Baseline in Pre-dose Trough FEV1 | 26 weeks | Trough FEV1 is defined as the average of the pre-dose FEV1 measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FEV1 measurements at 23h15min and 23h45min after dosing at Day 181. Baseline FEV1 is considered the Day 1 average of pre-dose measurements. |
| Annualized Rate of Moderate or Severe COPD Exacerbations | 26 weeks | Moderate or severe COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event. |
| Transition Dyspnea Index (TDI) Score | 12 weeks | Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea. The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline. |
| Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication | Baseline, 26 weeks | Change from baseline in mean daily number of puffs of rescue medication (number of puffs taken in the previous 12 hours) over 26 weeks of treatment. |
| Mean Change From Baseline in Forced Vital Capacity (FVC) | Baseline, 26 weeks | Change from baseline in forced vital capacity following 26 weeks of treatment. Trough FVC is defined as the average of the pre-dose FVC measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FVC measurements at 23h15min and 23h45min after dosing at Day 181. Baseline is considered the Day 1 average of pre-dose measurements. |
| Mean Change From Baseline in St. George's Respiratory Questionnaire | Baseline, 12 weeks | The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity; Part II covers Activity and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. |
Countries
Argentina, Austria, Belgium, Bulgaria, Canada, Croatia, Czechia, Denmark, Estonia, Germany, Greece, Hungary, Latvia, Lithuania, Netherlands, Poland, Romania, Serbia, Slovakia, Spain, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| QVA149 110/50 μg capsules o.d. for inhalation | 527 |
| Tiotropium + Salmeterol/Fluticasone tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.) | 526 |
| Total | 1,053 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 17 | 15 |
| Overall Study | Death | 3 | 4 |
| Overall Study | Lack of Efficacy | 7 | 2 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Non-compliance with study treatment | 1 | 0 |
| Overall Study | Patient/guardian decision | 32 | 18 |
| Overall Study | Physician Decision | 3 | 3 |
| Overall Study | Protocol deviation | 2 | 3 |
| Overall Study | Sponsor decision | 1 | 0 |
| Overall Study | Technical problems | 4 | 7 |
Baseline characteristics
| Characteristic | Tiotropium + Salmeterol/Fluticasone | Total | QVA149 |
|---|---|---|---|
| Age, Continuous | 65.2 Years STANDARD_DEVIATION 7.62 | 65.3 Years STANDARD_DEVIATION 7.8 | 65.4 Years STANDARD_DEVIATION 7.99 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 523 Participants | 1049 Participants | 526 Participants |
| Sex: Female, Male Female | 161 Participants | 310 Participants | 149 Participants |
| Sex: Female, Male Male | 365 Participants | 743 Participants | 378 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 527 | 5 / 526 |
| other Total, other adverse events | 398 / 527 | 392 / 526 |
| serious Total, serious adverse events | 32 / 527 | 34 / 526 |
Outcome results
Primary
Mean Change From Baseline in Post-dose Trough FEV1
Mean change from baseline in post-dose trough forced expiratory volume in 1 second (FEV1) following 26 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values measured at 23 hr 15 min and 23 hr 45 min after the morning dose taken at site on Day 181. Baseline FEV1 is defined as the average of the pre-dose FEV1 measured at -45 min and -15 min at Day 1.
Time frame: Baseline, 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Mean Change From Baseline in Post-dose Trough FEV1 | -0.029 Liters | Standard Error 0.0119 |
| Tiotropium + Salmeterol/Fluticasone | Mean Change From Baseline in Post-dose Trough FEV1 | -0.003 Liters | Standard Error 0.0115 |
p-value: 0.040495% CI: [-0.053, 0.001]Mixed Model for Repeated Measures Analys
Secondary
Annualized Rate of COPD Exacerbations Requiring Hospitalisation
COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event.
Time frame: 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 | Annualized Rate of COPD Exacerbations Requiring Hospitalisation | 0.001 COPD Exacerbations/year |
| Tiotropium + Salmeterol/Fluticasone | Annualized Rate of COPD Exacerbations Requiring Hospitalisation | 0.001 COPD Exacerbations/year |
p-value: 0.966595% CI: [0.44, 2.34]Generalized Linear Model Analysis
Secondary
Annualized Rate of COPD Exacerbations Requiring Treatment With Systemic Glucocorticosteroids and/or Antibiotics, Moderate Exacerbations Only
COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event
Time frame: 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 | Annualized Rate of COPD Exacerbations Requiring Treatment With Systemic Glucocorticosteroids and/or Antibiotics, Moderate Exacerbations Only | 0.47 COPD Exacerbations/year |
| Tiotropium + Salmeterol/Fluticasone | Annualized Rate of COPD Exacerbations Requiring Treatment With Systemic Glucocorticosteroids and/or Antibiotics, Moderate Exacerbations Only | 0.44 COPD Exacerbations/year |
p-value: 0.565195% CI: [0.82, 1.43]Generalized Linear Model Analysis
Secondary
Annualized Rate of Moderate or Severe COPD Exacerbations
Moderate or severe COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event.
Time frame: 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QVA149 | Annualized Rate of Moderate or Severe COPD Exacerbations | 0.52 COPD exacerbations/year |
| Tiotropium + Salmeterol/Fluticasone | Annualized Rate of Moderate or Severe COPD Exacerbations | 0.48 COPD exacerbations/year |
p-value: 0.580295% CI: [0.83, 1.4]Generalized Linear Model Analysis
Secondary
Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication
Change from baseline in mean daily number of puffs of rescue medication (number of puffs taken in the previous 12 hours) over 26 weeks of treatment.
Time frame: Baseline, 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication | -0.307 Number of puffs per day | Standard Error 0.1006 |
| Tiotropium + Salmeterol/Fluticasone | Change From Baseline in the Mean Daily Number of Puffs of Rescue Medication | -0.484 Number of puffs per day | Standard Error 0.0983 |
p-value: 0.064195% CI: [-0.01, 0.365]Linear Mixed Model Analysis
Secondary
Mean Change From Baseline in Forced Vital Capacity (FVC)
Change from baseline in forced vital capacity following 26 weeks of treatment. Trough FVC is defined as the average of the pre-dose FVC measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FVC measurements at 23h15min and 23h45min after dosing at Day 181. Baseline is considered the Day 1 average of pre-dose measurements.
Time frame: Baseline, 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Mean Change From Baseline in Forced Vital Capacity (FVC) | -0.030 Liters | Standard Error 0.0192 |
| Tiotropium + Salmeterol/Fluticasone | Mean Change From Baseline in Forced Vital Capacity (FVC) | -0.048 Liters | Standard Error 0.0186 |
p-value: 0.410795% CI: [-0.025, 0.061]Mixed Model for Repeated Measures Analys
Secondary
Mean Change From Baseline in Pre-dose Trough FEV1
Trough FEV1 is defined as the average of the pre-dose FEV1 measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FEV1 measurements at 23h15min and 23h45min after dosing at Day 181. Baseline FEV1 is considered the Day 1 average of pre-dose measurements.
Time frame: 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Mean Change From Baseline in Pre-dose Trough FEV1 | -0.029 Liters | Standard Error 0.0119 |
| Tiotropium + Salmeterol/Fluticasone | Mean Change From Baseline in Pre-dose Trough FEV1 | -0.003 Liters | Standard Error 0.0115 |
p-value: 0.057395% CI: [-0.053, 0.001]Mixed Model for Repeated Measures Analys
Secondary
Mean Change From Baseline in St. George's Respiratory Questionnaire
The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity; Part II covers Activity and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.
Time frame: Baseline, 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Mean Change From Baseline in St. George's Respiratory Questionnaire | -1.0 Score on a scale | Standard Error 0.54 |
| Tiotropium + Salmeterol/Fluticasone | Mean Change From Baseline in St. George's Respiratory Questionnaire | -2.5 Score on a scale | Standard Error 0.52 |
p-value: 0.022195% CI: [0.2, 2.6]Mixed Model for Repeated measures Analys
Secondary
Mean Change From Baseline in St. George's Respiratory Questionnaire
The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status. The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: Part I covers Symptoms and is concerned with respiratory symptoms, their frequency and severity; Part II covers Activity and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with Impacts, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these 3 subscales and a Total score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.
Time frame: Baseline, 12 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Mean Change From Baseline in St. George's Respiratory Questionnaire | -0.7 Score on a scale | Standard Error 0.53 |
| Tiotropium + Salmeterol/Fluticasone | Mean Change From Baseline in St. George's Respiratory Questionnaire | -2.5 Score on a scale | Standard Error 0.51 |
p-value: 0.002295% CI: [0.7, 3]Mixed Model for Repeated Measures Analys
Secondary
Transition Dyspnea Index (TDI) Score
Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea. The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline.
Time frame: 12 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Transition Dyspnea Index (TDI) Score | 1.177 Score on a scale | Standard Error 0.1558 |
| Tiotropium + Salmeterol/Fluticasone | Transition Dyspnea Index (TDI) Score | 1.418 Score on a scale | Standard Error 0.1508 |
p-value: 0.172495% CI: [-0.587, 0.105]Mixed Model for Repeated Measures Analys
Secondary
Transition Dyspnea Index (TDI) Score
Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea. The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline.
Time frame: 26 weeks
Population: Full Analysis Set: The full analysis set included all randomized participants who received at least one dose of study drug. Patients in the FAS were analyzed according to the treatment they were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Transition Dyspnea Index (TDI) Score | 1.382 Score on a scale | Standard Error 0.1567 |
| Tiotropium + Salmeterol/Fluticasone | Transition Dyspnea Index (TDI) Score | 1.671 Score on a scale | Standard Error 0.1519 |
p-value: 0.105595% CI: [-0.638, 0.061]Mixed Model for Repated Measures Analysi